FAM135B

Chr 8

family with sequence similarity 135 member B

Also known as: C8ORFK32

NCBI Gene: 51059 ENSG00000147724 UniProt: Q49AJ0 OMIM: 621534

The FAM135B protein is predicted to be involved in lipid metabolism. Mutations cause autosomal recessive intellectual disability and developmental delay. This gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.22), indicating intolerance to protein-truncating mutations.

OMIM ResearchSummary from RefSeq

Predicted to be involved in lipid metabolic process. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.22

Clinical Summary— FAM135B

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

175 VUS of 209 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.22LOEUF

pLI 1.000

Z-score 6.30

OE 0.12 (0.07–0.22)

Highly constrained

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

Missense Constraint?

0.97Z-score

OE missense 0.90 (0.85–0.96)

697 obs / 772.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.07–0.22)

0≤0.351.4

Missense OE?0.90 (0.85–0.96)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 7 / 59.3Missense obs/exp: 697 / 772.5Syn Z: -0.80

This gene — mechanism propensity

0.3296th %ile

GOF

0.3689th %ile

LOF

0.70top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.22

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

209 submitted variants in ClinVar

ClinVar

Classification Summary

VUS175

Likely Benign17

Benign5

175

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	174	0	0	175
Likely Benign	0	12	0	5	17
Benign	0	3	1	1	5
Total	1	189	1	6	197

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

View in ClinVar →

53 pathogenic / likely-pathogenic (of 62) ClinVar copy-number / structural variants overlap FAM135B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →