Is EFHB p.Val480Ala (c.1439T>C) pathogenic?

EFHB p.Val480Ala (c.1439T>C) is classified Uncertain significance in EFHB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). AlphaMissense: ambiguous (0.3478); Very rare (popmax 0.00171%, amr).

How common is EFHB p.Val480Ala (c.1439T>C) in the general population?

EFHB p.Val480Ala (c.1439T>C) is very rare (popmax 0.00171%, amr) (gnomAD).

What do computational predictors say about EFHB p.Val480Ala (c.1439T>C)?

AlphaMissense predicts ambiguous (score 0.3478) — an in-silico prediction, not a clinical call.

EFHB p.Val480Ala

c.1439T>C · VCV4247067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3478 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00171%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3478	ambiguous
REVEL	0.147	moderately benign-leaning
SaProt	LLR -8.35	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 54 kb · p 0.007 · regional, not allelic
Overall
CADD	17.81	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 0.00171% Admixed American · 1/58,638 alleles

Overall 0.000125% 2/1,604,950 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00171%	58,638
Remaining individualsnot grpmax-eligible	0.00161%	62,154

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: EFHB
Protein: p.Val480Ala
Coding: c.1439T>C
MANE Select: NM_144715
Type: single nucleotide variant
Location: chr3:19899495 (GRCh38)
Gene constraint: LOEUF 1.244 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.23 · 2 PDB

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

Similar variants

EFHB p.Lys557Gln Likely benign ★★ same type
EFHB p.Ala145Ser Uncertain significance ★ ⚠ same type
EFHB p.Ala264Pro Uncertain significance ★ ⚠ same type
EFHB p.Ala291Thr Uncertain significance ★ same type
EFHB p.Ala460Ser Uncertain significance ★ ⚠ same type
EFHB p.Ala550Glu Uncertain significance ★ ⚠ same type
EFHB p.Ala623Thr Uncertain significance ★ ⚠ same type
EFHB p.Ala623Val 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/efhb-p-val480ala (accessed [today's date]).

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