Is CERS6 p.Val269Met (c.805G>A) pathogenic?

CERS6 p.Val269Met (c.805G>A) is classified Likely benign in CERS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-06). AlphaMissense: likely benign (0.0803); Ultra-rare (popmax 0.0417%, amr).

How common is CERS6 p.Val269Met (c.805G>A) in the general population?

CERS6 p.Val269Met (c.805G>A) is ultra-rare (popmax 0.0417%, amr) (gnomAD).

What do computational predictors say about CERS6 p.Val269Met (c.805G>A)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

CERS6 p.Val269Met

c.805G>A · rs373359187 · VCV2358658

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -8.39	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 2	GERP -3, phastCons 0.65
Regional constraint	o/e 0.89	unconstrained · MANE · 313 kb · p 0.015 · regional, not allelic
Overall
CADD	15.09	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 0.0417% Admixed American · 25/59,972 alleles

Filtering AF 0.0289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0248%

Overall 0.00316% 51/1,613,478 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0417%	2,399
African / African-American	0.012%	8,318
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,592
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)	0.00119%	84,266
South Asian	0.0011%	91,042

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: CERS6
Protein: p.Val269Met
Coding: c.805G>A
MANE Select: NM_203463
dbSNP: rs373359187
Type: single nucleotide variant
Location: chr2:168717938 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI 0.43 (gnomAD)
Structure: AlphaFold pLDDT 87.97 · 3 PDB
Residue 269: the tlc domain; an α-helix

Full CERS6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CERS6 p.Ala30Ser Uncertain significance ★ ⚠ same type
CERS6 p.Ala326Val Uncertain significance ★ ⚠ same type
CERS6 p.Ala362Val Uncertain significance ★ ⚠ same type
CERS6 p.Ala6Val Uncertain significance ★ ⚠ same type
CERS6 p.Arg121Cys Uncertain significance ★ ⚠ same type
CERS6 p.Asn10Lys Uncertain significance ★ ⚠ same type
CERS6 p.Asn122Ser Uncertain significance ★ ⚠ same type
CERS6 p.Asn168Lys 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/cers6-p-val269met (accessed [today's date]).

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