Is EFNB1 p.Val331Phe (c.991G>T) pathogenic?

EFNB1 p.Val331Phe (c.991G>T) is classified Uncertain significance in EFNB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-14). AlphaMissense: likely pathogenic (0.9738); Very rare (popmax 0.00313%, nfe).

How common is EFNB1 p.Val331Phe (c.991G>T) in the general population?

EFNB1 p.Val331Phe (c.991G>T) is very rare (popmax 0.00313%, nfe) (gnomAD).

What do computational predictors say about EFNB1 p.Val331Phe (c.991G>T)?

AlphaMissense predicts likely pathogenic (score 0.9738) — an in-silico prediction, not a clinical call.

EFNB1 p.Val331Phe

c.991G>T · rs376262683 · VCV1313958

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00313%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9738	likely pathogenic
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -11.82	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 11 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00313% European (non-Finnish) · 28/894,835 alleles

Filtering AF 0.00217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00187%

Overall 0.00232% 28/1,209,302 alleles · very rare

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: EFNB1
Protein: p.Val331Phe
Coding: c.991G>T
MANE Select: NM_004429
dbSNP: rs376262683
Type: single nucleotide variant
Location: chrX:68840604 (GRCh38)
Structure: AlphaFold pLDDT 71.68 · 1 PDB

Full EFNB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFNB1 p.Val331Ile Uncertain significance ★ ⚠ same residue
EFNB1 c.128+1G>C Likely pathogenic ★★ same type
EFNB1 c.499+1G>A Pathogenic/Likely pathogenic ★★ same type
EFNB1 p.Arg66Ter Pathogenic ★★ same type
EFNB1 p.Gln175Ter Likely pathogenic ★★ same type
EFNB1 p.Gln85Ter Pathogenic ★★ same type
EFNB1 p.Gly10= Pathogenic ★★ same type
EFNB1 p.Gly151Ser Pathogenic ★★ 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/efnb1-p-val331phe (accessed [today's date]).

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