Is EFHC2 p.Arg608His (c.1823G>A) pathogenic?

EFHC2 p.Arg608His (c.1823G>A) is classified Uncertain significance in EFHC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely benign (0.1085); Very rare (popmax 0.00874%, afr).

How common is EFHC2 p.Arg608His (c.1823G>A) in the general population?

EFHC2 p.Arg608His (c.1823G>A) is very rare (popmax 0.00874%, afr) (gnomAD).

What do computational predictors say about EFHC2 p.Arg608His (c.1823G>A)?

AlphaMissense predicts likely benign (score 0.1085) — an in-silico prediction, not a clinical call.

EFHC2 p.Arg608His

c.1823G>A · rs746208476 · VCV3087551

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1085 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00874%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1085	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -7.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.41	GERP 1.4
Regional constraint	o/e 0.91	unconstrained · MANE · 195 kb · p 0.037 · regional, not allelic
Overall
CADD	11.32	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 0.00874% African / African-American · 5/57,237 alleles

Filtering AF 0.00338% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00215%

Overall 0.000914% 11/1,204,024 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00874%	11,447
East Asian	0.00593%	16,860
Admixed American	0.00221%	45,191
European (non-Finnish)	0.000336%	297,445

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.Arg608His
Coding: c.1823G>A
MANE Select: NM_025184
dbSNP: rs746208476
Type: single nucleotide variant
Location: chrX:44178493 (GRCh38)
Structure: AlphaFold pLDDT 79.83 · 4 PDB

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

Similar variants

EFHC2 p.Arg608Cys Uncertain significance ★ ⚠ same residue
EFHC2 p.Arg608Leu Uncertain significance ★ ⚠ same residue
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

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-arg608his (accessed [today's date]).

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