SLC16A2

Chr X

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

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 ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismLOEUF 0.22

Clinical Summary— SLC16A2

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Gene-Disease Validity (ClinGen)

Allan-Herndon-Dudley syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

83 unique Pathogenic / Likely Pathogenic· 124 VUS of 300 total submissions

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Clinical Trials

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

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GeneReview available — SLC16A2

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE0.00 (0.00–0.22)

0≤0.351.4

Missense OE0.56 (0.48–0.64)

0≤0.61.4

Synonymous OE0.88

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

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.

LOF40% of P/LP variants are LoF · LOEUF 0.22

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.