Is EFHC2 p.Arg522His (c.1565G>A) pathogenic?

EFHC2 p.Arg522His (c.1565G>A) is classified Uncertain significance in EFHC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.07); Ultra-rare (popmax 0.0103%, nfe).

How common is EFHC2 p.Arg522His (c.1565G>A) in the general population?

EFHC2 p.Arg522His (c.1565G>A) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

What do computational predictors say about EFHC2 p.Arg522His (c.1565G>A)?

AlphaMissense predicts likely benign (score 0.07) — an in-silico prediction, not a clinical call.

EFHC2 p.Arg522His

c.1565G>A · rs772087258 · VCV2262551

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.07 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.07	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.34	GERP -6.3
Regional constraint	o/e 0.91	unconstrained · MANE · 195 kb · p 0.037 · regional, not allelic
Overall
CADD	0.08	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 0.0103% European (non-Finnish) · 91/880,127 alleles

Filtering AF 0.00857% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00794%

Overall 0.00796% 94/1,181,308 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,672
Remaining individualsnot grpmax-eligible	0.0043%	23,239
African / African-American	0.00177%	56,603

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.Arg522His
Coding: c.1565G>A
MANE Select: NM_025184
dbSNP: rs772087258
Type: single nucleotide variant
Location: chrX:44232536 (GRCh38)
Structure: AlphaFold pLDDT 79.83 · 4 PDB
Residue 522: the dm10 3 domain

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.Arg133His 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

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-arg522his (accessed [today's date]).

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