Is EFS p.Val471Met (c.1411G>A) pathogenic?

EFS p.Val471Met (c.1411G>A) is classified Uncertain significance in EFS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). AlphaMissense: ambiguous (0.4571); Very rare (popmax 0.00267%, afr).

How common is EFS p.Val471Met (c.1411G>A) in the general population?

EFS p.Val471Met (c.1411G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about EFS p.Val471Met (c.1411G>A)?

AlphaMissense predicts ambiguous (score 0.4571) — an in-silico prediction, not a clinical call.

EFS p.Val471Met

c.1411G>A · rs201776896 · VCV2457505

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4571 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
AlphaMissense	0.4571	ambiguous
REVEL	0.364	indeterminate
SaProt	LLR -10.26	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.25 · evaluated, not missing
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	26.6	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 0.00267% African / African-American · 2/74,930 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00632% 102/1,613,824 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.216%	462
Remaining individualsnot grpmax-eligible	0.0208%	4,806
African / African-Americangrpmax	0.00267%	37,465
South Asian	0.0022%	45,526
European (non-Finnish)	0.00178%	56,190

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val471Met
Coding: c.1411G>A
MANE Select: NM_005864
dbSNP: rs201776896
Type: single nucleotide variant
Location: chr14:23357501 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.71
Residue 471: the 'divergent helix-loop-helix motif' region

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.Ala495Pro 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-val471met (accessed [today's date]).

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