Is EFHD2 p.Ala63Ser (c.187G>T) pathogenic?

EFHD2 p.Ala63Ser (c.187G>T) is classified Uncertain significance in EFHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.0893); Very rare (popmax 0.0023%, eas).

How common is EFHD2 p.Ala63Ser (c.187G>T) in the general population?

EFHD2 p.Ala63Ser (c.187G>T) is very rare (popmax 0.0023%, eas) (gnomAD).

What do computational predictors say about EFHD2 p.Ala63Ser (c.187G>T)?

AlphaMissense predicts likely benign (score 0.0893) — an in-silico prediction, not a clinical call.

EFHD2 p.Ala63Ser

c.187G>T · VCV4247102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0893	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 16 kb · p 0.00057 · regional, not allelic
Overall
CADD	21.6	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 0.0023% East Asian · 1/43,396 alleles

Overall 0.000207% 3/1,449,336 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0023%	43,396
Admixed American	0.00169%	59,110
European (non-Finnish)	8.51e-05%	1,175,530

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: EFHD2
Protein: p.Ala63Ser
Coding: c.187G>T
Type: single nucleotide variant
Location: chr1:15410158 (GRCh38)

Full EFHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/efhd2-p-ala63ser (accessed [today's date]).

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