Is EFCAB14 p.Asp255His (c.763G>C) pathogenic?

EFCAB14 p.Asp255His (c.763G>C) is classified Uncertain significance in EFCAB14 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: likely benign (0.1369); Ultra-rare (popmax 0.033%, mid).

How common is EFCAB14 p.Asp255His (c.763G>C) in the general population?

EFCAB14 p.Asp255His (c.763G>C) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about EFCAB14 p.Asp255His (c.763G>C)?

AlphaMissense predicts likely benign (score 0.1369) — an in-silico prediction, not a clinical call.

EFCAB14 p.Asp255His

c.763G>C · rs200564580 · VCV3087420

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1369 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1369	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -7.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 40 kb · p 0.079 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.033% Middle Eastern · 2/6,058 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.012%

Overall 0.0108% 175/1,613,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,029
European (non-Finnish)	0.0145%	6,900
Remaining individualsnot grpmax-eligible	0.0016%	62,490
Finnishnot grpmax-eligible	0.00156%	64,038

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: EFCAB14
Protein: p.Asp255His
Coding: c.763G>C
MANE Select: NM_014774
dbSNP: rs200564580
Type: single nucleotide variant
Location: chr1:46689619 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.45

Full EFCAB14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFCAB14 p.Ala196Thr Uncertain significance ★ ⚠ same type
EFCAB14 p.Ala393Thr Uncertain significance ★ ⚠ same type
EFCAB14 p.Ala423Val Uncertain significance ★ ⚠ same type
EFCAB14 p.Ala87Val Uncertain significance ★ ⚠ same type
EFCAB14 p.Arg110Gln Uncertain significance ★ ⚠ same type
EFCAB14 p.Arg33Leu Uncertain significance ★ ⚠ same type
EFCAB14 p.Arg388Ser Uncertain significance ★ ⚠ same type
EFCAB14 p.Asn127Lys 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/efcab14-p-asp255his (accessed [today's date]).

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