Is CERS3 p.Ser177Phe (c.530C>T) pathogenic?

CERS3 p.Ser177Phe (c.530C>T) is classified Uncertain significance in CERS3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-03-06). AlphaMissense: ambiguous (0.4902); Ultra-rare (popmax 0.0334%, mid); Associated with Inborn genetic diseases.

What condition is associated with CERS3 p.Ser177Phe (c.530C>T)?

CERS3 p.Ser177Phe (c.530C>T) is associated with Inborn genetic diseases, autosomal recessive congenital ichthyosis 9 (ClinVar).

How common is CERS3 p.Ser177Phe (c.530C>T) in the general population?

CERS3 p.Ser177Phe (c.530C>T) is ultra-rare (popmax 0.0334%, mid) (gnomAD).

What do computational predictors say about CERS3 p.Ser177Phe (c.530C>T)?

AlphaMissense predicts ambiguous (score 0.4902) — an in-silico prediction, not a clinical call.

CERS3 p.Ser177Phe

c.530C>T · rs1178676096 · VCV800985

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4902 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4902	ambiguous
REVEL	0.867	moderately pathogenic-leaning
SaProt	LLR -11.42	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 99 kb · p 0.65 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0334% Middle Eastern · 2/5,994 alleles

Filtering AF 0.00588% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.000763% 12/1,572,230 alleles · ultra-rare exomes 12/1,420,060 · genomes 0/152,170 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0334%	2,997
Remaining individualsnot grpmax-eligible	0.00329%	30,409
South Asian	0.00239%	41,804
European (non-Finnish)	0.000515%	194,182

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CERS3
Protein: p.Ser177Phe
Coding: c.530C>T
MANE Select: NM_001378789
dbSNP: rs1178676096
Type: single nucleotide variant
Location: chr15:100476165 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.52
Residue 177: the tlc domain

Full CERS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive congenital ichthyosis 9

Similar variants

CERS3 c.466-1G>T Likely pathogenic ★★ same condition
CERS3 p.Arg75Ter Likely pathogenic ★★ same condition
CERS3 p.Arg275Cys Uncertain significance ★★ ⚠ same condition
CERS3 c.845+53C>T Benign ★★ same condition
CERS3 c.999+60G>A Benign ★★ same condition
CERS3 c.*75C>A Benign ★★ same condition
CERS3 p.Arg370Gly Benign ★★ same condition
CERS3 p.Arg53= Benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cers3-p-ser177phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown