Is EFS p.Ala495Pro (c.1483G>C) pathogenic?

EFS p.Ala495Pro (c.1483G>C) is classified Uncertain significance in EFS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-02). AlphaMissense: likely pathogenic (0.6901); Very rare (popmax 0.00772%, nfe).

How common is EFS p.Ala495Pro (c.1483G>C) in the general population?

EFS p.Ala495Pro (c.1483G>C) is very rare (popmax 0.00772%, nfe) (gnomAD).

What do computational predictors say about EFS p.Ala495Pro (c.1483G>C)?

AlphaMissense predicts likely pathogenic (score 0.6901) — an in-silico prediction, not a clinical call.

EFS p.Ala495Pro

c.1483G>C · rs778972074 · VCV2382755

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6901 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00772%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6901	likely pathogenic
REVEL	0.171	moderately benign-leaning
SaProt	LLR -9.32	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 7,796 bp · p 0.65 · regional, not allelic
Overall
CADD	26.1	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 0.00772% European (non-Finnish) · 91/1,179,382 alleles

Filtering AF 0.0064% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00592%

Overall 0.00583% 94/1,612,580 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00772%	12,960
Remaining individualsnot grpmax-eligible	0.00481%	20,807

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: EFS
Protein: p.Ala495Pro
Coding: c.1483G>C
MANE Select: NM_005864
dbSNP: rs778972074
Type: single nucleotide variant
Location: chr14:23357429 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.71

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

Similar variants

EFS p.Pro141= Benign ★★ same type
EFS p.Ala167Thr Uncertain significance ★ ⚠ same type
EFS p.Ala186Val Uncertain significance ★ ⚠ same type
EFS p.Ala219Asp Uncertain significance ★ ⚠ same type
EFS p.Ala262Ser Uncertain significance ★ ⚠ same type
EFS p.Ala285Ser Uncertain significance ★ ⚠ same type
EFS p.Ala40Val Uncertain significance ★ ⚠ same type
EFS p.Ala498Val 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/efs-p-ala495pro (accessed [today's date]).

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