Is CERS4 p.Pro177Arg (c.530C>G) pathogenic?

CERS4 p.Pro177Arg (c.530C>G) is classified Uncertain significance in CERS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-22). AlphaMissense: likely benign (0.1144); Very rare (popmax 0.00534%, afr).

How common is CERS4 p.Pro177Arg (c.530C>G) in the general population?

CERS4 p.Pro177Arg (c.530C>G) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CERS4 p.Pro177Arg (c.530C>G)?

AlphaMissense predicts likely benign (score 0.1144) — an in-silico prediction, not a clinical call.

CERS4 p.Pro177Arg

c.530C>G · rs1481960818 · VCV2285140

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1144 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1144	likely benign
REVEL	0.363	indeterminate
SaProt	LLR -9.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.29	GERP -0.75, phastCons 0.02
Regional constraint	o/e 1.13	unconstrained · MANE · 11 kb · p 0.0051 · regional, not allelic
Overall
CADD	15.76	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,844 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,612,126 alleles · very rare

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: CERS4
Protein: p.Pro177Arg
Coding: c.530C>G
MANE Select: NM_024552
dbSNP: rs1481960818
Type: single nucleotide variant
Location: chr19:8256628 (GRCh38)
Gene constraint: LOEUF 1.472 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.92
Residue 177: the tlc domain

Full CERS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CERS4 p.Ala82Thr Likely benign ★★ same type
CERS4 p.Leu194= Benign ★★ same type
CERS4 p.Ala162Val Uncertain significance ★ ⚠ same type
CERS4 p.Ala373Thr Uncertain significance ★ ⚠ same type
CERS4 p.Ala46Val Uncertain significance ★ ⚠ same type
CERS4 p.Arg116Gln Uncertain significance ★ ⚠ same type
CERS4 p.Arg121His Uncertain significance ★ ⚠ same type
CERS4 p.Arg203Cys Uncertain significance ★ ⚠ 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/cers4-p-pro177arg (accessed [today's date]).

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