Is EFHB p.Ala264Pro (c.790G>C) pathogenic?

EFHB p.Ala264Pro (c.790G>C) is classified Uncertain significance in EFHB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely pathogenic (0.7714); Very rare (popmax 0.000512%, nfe).

How common is EFHB p.Ala264Pro (c.790G>C) in the general population?

EFHB p.Ala264Pro (c.790G>C) is very rare (popmax 0.000512%, nfe) (gnomAD).

What do computational predictors say about EFHB p.Ala264Pro (c.790G>C)?

AlphaMissense predicts likely pathogenic (score 0.7714) — an in-silico prediction, not a clinical call.

EFHB p.Ala264Pro

c.790G>C · VCV4663277

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7714 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000512%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7714	likely pathogenic · top 8% in EFHB
REVEL	0.306	indeterminate
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.23	acceptor loss · deltas
Pangolin	Δ0.23	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 54 kb · p 0.007 · regional, not allelic
Overall
CADD	28.2	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 0.000512% European (non-Finnish) · 6/1,171,754 alleles

Filtering AF 0.000184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000377% 6/1,590,662 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: EFHB
Protein: p.Ala264Pro
Coding: c.790G>C
MANE Select: NM_144715
Type: single nucleotide variant
Location: chr3:19920567 (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.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
EFHB p.Ala749Ser 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-ala264pro (accessed [today's date]).

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