Is CERS2 p.Arg377Pro (c.1130G>C) pathogenic?

CERS2 p.Arg377Pro (c.1130G>C) is classified Uncertain significance in CERS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.2161); Very rare (popmax 0.00884%, sas).

How common is CERS2 p.Arg377Pro (c.1130G>C) in the general population?

CERS2 p.Arg377Pro (c.1130G>C) is very rare (popmax 0.00884%, sas) (gnomAD).

What do computational predictors say about CERS2 p.Arg377Pro (c.1130G>C)?

AlphaMissense predicts likely benign (score 0.2161) — an in-silico prediction, not a clinical call.

CERS2 p.Arg377Pro

c.1130G>C · rs779228104 · VCV3143155

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2161 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00884%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2161	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP -3.6, phastCons 0.002
Regional constraint	o/e 0.80	unconstrained · MANE · 670 bp · p 0.015 · regional, not allelic
Overall
CADD	19.22	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 0.00884% South Asian · 8/90,542 alleles

Filtering AF 0.00698% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00689% 111/1,610,470 alleles · very rare exomes 100/1,458,350 · genomes 11/152,120 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00884%	11,318
European (non-Finnish)	0.00831%	12,032
Remaining individualsnot grpmax-eligible	0.00321%	31,167
Admixed American	0.00171%	58,562
Finnishnot grpmax-eligible	0.00156%	63,996
African / African-American	0.00134%	74,602

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: CERS2
Protein: p.Arg377Pro
Coding: c.1130G>C
MANE Select: NM_022075
dbSNP: rs779228104
Type: single nucleotide variant
Location: chr1:150966161 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 87.31
Residue 377: the 'disordered' region

Full CERS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CERS2 p.Ala152= Benign ★★ same type
CERS2 p.Ser199= Benign ★★ same type
CERS2 p.Tyr254= Benign ★★ same type
CERS2 p.Ala23Ser Uncertain significance ★ ⚠ same type
CERS2 p.Ala23Val Uncertain significance ★ ⚠ same type
CERS2 p.Ala34Thr Uncertain significance ★ same type
CERS2 p.Ala46Gly Uncertain significance ★ ⚠ same type
CERS2 p.Arg105Leu 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/cers2-p-arg377pro (accessed [today's date]).

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