Is EFHC2 p.Arg133His (c.398G>A) pathogenic?

EFHC2 p.Arg133His (c.398G>A) is classified Uncertain significance in EFHC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). AlphaMissense: likely pathogenic (0.6048); Ultra-rare (popmax 0.024%, eas).

How common is EFHC2 p.Arg133His (c.398G>A) in the general population?

EFHC2 p.Arg133His (c.398G>A) is ultra-rare (popmax 0.024%, eas) (gnomAD).

What do computational predictors say about EFHC2 p.Arg133His (c.398G>A)?

AlphaMissense predicts likely pathogenic (score 0.6048) — an in-silico prediction, not a clinical call.

EFHC2 p.Arg133His

c.398G>A · VCV3507018

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6048 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6048	likely pathogenic
REVEL	0.846	moderately pathogenic-leaning
SaProt	LLR -12.15	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 5.9	GERP 3.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 195 kb · p 0.037 · regional, not allelic
Overall
CADD	25.8	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 0.024% East Asian · 8/33,369 alleles

Filtering AF 0.0119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0087%

Overall 0.00118% 14/1,186,714 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.024%	4,171
South Asian	0.00385%	25,995
European (non-Finnish)	0.000453%	220,558

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: EFHC2
Protein: p.Arg133His
Coding: c.398G>A
MANE Select: NM_025184
Type: single nucleotide variant
Location: chrX:44261283 (GRCh38)
Structure: AlphaFold pLDDT 79.83 · 4 PDB
Residue 133: the dm10 1 domain; a β-strand

Full EFHC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFHC2 p.Glu506Lys Likely benign ★★ ⚠ same type
EFHC2 p.Glu507Gln Benign ★★ ⚠ same type
EFHC2 p.Ala549Gly Uncertain significance ★ ⚠ same type
EFHC2 p.Ala697Ser Uncertain significance ★ ⚠ same type
EFHC2 p.Arg135Gln Conflicting classifications of pathogenicity ★ ⚠ same type
EFHC2 p.Arg135Trp Uncertain significance ★ ⚠ same type
EFHC2 p.Arg163Gln Uncertain significance ★ ⚠ same type
EFHC2 p.Arg163Trp 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/efhc2-p-arg133his (accessed [today's date]).

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