Is CERS3 p.His294Arg (c.881A>G) pathogenic?

CERS3 p.His294Arg (c.881A>G) is classified Benign in CERS3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.074); Common (popmax 5.8%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CERS3 p.His294Arg (c.881A>G)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

CERS3 p.His294Arg

Q: How common is CERS3 p.His294Arg (c.881A>G) in the general population?

CERS3 p.His294Arg (c.881A>G) is common (popmax 5.8%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.881A>G · rs114065539 · VCV1178503

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.8%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	acceptor loss, 41 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 6.2	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 99 kb · p 0.65 · regional, not allelic
Overall
CADD	18.56	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 5.8% Admixed American · 3,460/59,702 alleles

Filtering AF 5.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.57%

Overall 0.487% 7,856/1,612,150 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	5.8%	17
South Asian	2.26%	44
East Asian	1.06%	94
Middle Eastern	0.925%	108
Remaining individualsnot grpmax-eligible	0.729%	137
African / African-American	0.441%	227
Ashkenazi Jewishnot grpmax-eligible	0.2%	501
European (non-Finnish)	0.0821%	1,218

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.His294Arg
Coding: c.881A>G
MANE Select: NM_001378789
dbSNP: rs114065539
Type: single nucleotide variant
Location: chr15:100456011 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.52
Residue 294: the tlc domain

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

Similar variants

CERS3 c.466-1G>T Likely pathogenic ★★ same type
CERS3 p.Arg75Ter Likely pathogenic ★★ same type
CERS3 p.Arg275Cys Uncertain significance ★★ ⚠ same type
CERS3 p.Ser177Phe Uncertain significance ★★ ⚠ same type
CERS3 c.174-81G>A Benign ★★ same type
CERS3 c.407+74C>T Benign ★★ same type
CERS3 c.465+65A>T Benign ★★ same type
CERS3 c.466-110G>T Benign ★★ same type

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-his294arg (accessed [today's date]).

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