Is CERS2 p.Val153Ile (c.457G>A) pathogenic?

CERS2 p.Val153Ile (c.457G>A) is classified Uncertain significance in CERS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-06). AlphaMissense: likely benign (0.1323); Ultra-rare (popmax 0.0116%, nfe).

How common is CERS2 p.Val153Ile (c.457G>A) in the general population?

CERS2 p.Val153Ile (c.457G>A) is ultra-rare (popmax 0.0116%, nfe) (gnomAD).

What do computational predictors say about CERS2 p.Val153Ile (c.457G>A)?

AlphaMissense predicts likely benign (score 0.1323) — an in-silico prediction, not a clinical call.

CERS2 p.Val153Ile

c.457G>A · VCV3491029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1323 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0116%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1323	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -7.59	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 7.6	GERP 0.63, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 1,991 bp · p 3.1e-05 · regional, not allelic
Overall
CADD	23.3	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 0.0116% European (non-Finnish) · 137/1,179,622 alleles

Filtering AF 0.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0094%

Overall 0.00923% 149/1,613,598 alleles · ultra-rare exomes 130/1,461,406 · genomes 19/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0116%	8,610
Finnishnot grpmax-eligible	0.0109%	9,145
Remaining individualsnot grpmax-eligible	0.0048%	20,821
Admixed American	0.00167%	60,002
African / African-American	0.00133%	74,930

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.Val153Ile
Coding: c.457G>A
MANE Select: NM_022075
Type: single nucleotide variant
Location: chr1:150967831 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 87.31
Residue 153: the tlc domain

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-val153ile (accessed [today's date]).

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