SLC16A2

Chr XX-linked

solute carrier family 16 member 2

Also known as: AHDS, DXS128, DXS128E, MCT 7, MCT 8, MCT7, MCT8, MRX22

NCBI Gene: 6567 ENSG00000147100 UniProt: P36021 OMIM: 300095

The protein functions as a thyroid hormone transporter that facilitates cellular import of T4, T3, reverse T3, and T2, playing a crucial role in central nervous system development. Loss-of-function mutations cause Allan-Herndon-Dudley syndrome, an X-linked disorder characterized by severe psychomotor retardation in affected males, while carrier females typically show no neurological defects and only mild thyroid abnormalities. The high constraint scores (pLI 0.99, LOEUF 0.22) reflect the gene's intolerance to loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an integral membrane protein that functions as a transporter of thyroid hormone. The encoded protein facilitates the cellular importation of thyroxine (T4), triiodothyronine (T3), reverse triiodothyronine (rT3) and diidothyronine (T2). This gene is expressed in many tissues and likely plays an important role in the development of the central nervous system. Loss of function mutations in this gene are associated with psychomotor retardation in males while females exhibit no neurological defects and more moderate thyroid-deficient phenotypes. This gene is subject to X-chromosome inactivation. Mutations in this gene are the cause of Allan-Herndon-Dudley syndrome. [provided by RefSeq, Mar 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismX-linkedLOEUF 0.221 OMIM phenotype

Clinical Summary— SLC16A2

🧬

Gene-Disease Validity (ClinGen)

Allan-Herndon-Dudley syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

105 unique Pathogenic / Likely Pathogenic· 172 VUS of 462 total submissions

💊

Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — SLC16A2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.22LOEUF

pLI 0.988

Z-score 3.39

OE 0.00 (0.00–0.22)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.38Z-score

OE missense 0.56 (0.48–0.64)

126 obs / 227.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.22)

0≤0.351.4

Missense OE?0.56 (0.48–0.64)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 0 / 13.4Missense obs/exp: 126 / 227.0Syn Z: 0.89

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSLC16A2-related thyroid hormone cell transporter deficiencyLOFXLR

This gene — mechanism propensity

0.3991th %ile

GOF

0.7029th %ile

LOF

0.54top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF63% of P/LP variants are LoF · LOEUF 0.22 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

462 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic63

Likely Pathogenic42

VUS172

Likely Benign107

Benign22

Conflicting16

Pathogenic

Likely Pathogenic

172

VUS

107

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	47	12	4	0	63
Likely Pathogenic	19	20	2	1	42
VUS	1	150	18	3	172
Likely Benign	0	19	26	62	107
Benign	0	8	4	10	22
Conflicting	—				16
Total	67	209	54	76	422

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

65 pathogenic / likely-pathogenic (of 74) ClinVar copy-number / structural variants overlap SLC16A2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →