Is EFHD2 p.Arg151Gln (c.452G>A) pathogenic?

EFHD2 p.Arg151Gln (c.452G>A) is classified Uncertain significance in EFHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-14). AlphaMissense: ambiguous (0.5579); Ultra-rare (popmax 0.0137%, afr).

How common is EFHD2 p.Arg151Gln (c.452G>A) in the general population?

EFHD2 p.Arg151Gln (c.452G>A) is ultra-rare (popmax 0.0137%, afr) (gnomAD).

What do computational predictors say about EFHD2 p.Arg151Gln (c.452G>A)?

AlphaMissense predicts ambiguous (score 0.5579) — an in-silico prediction, not a clinical call.

EFHD2 p.Arg151Gln

c.452G>A · VCV3507024

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5579 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, afr)

Computational evidence

Protein change
AlphaMissense	0.5579	ambiguous
REVEL	0.514	indeterminate
SaProt	LLR -8.91	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 1,199 bp · p 9.1e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0137% African / African-American · 10/72,810 alleles

Filtering AF 0.00742% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00564%

Overall 0.000885% 14/1,581,076 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0137%	7,281
Remaining individualsnot grpmax-eligible	0.00328%	30,528
European (non-Finnish)	0.000172%	582,798

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.Arg151Gln
Coding: c.452G>A
MANE Select: NM_024329
Type: single nucleotide variant
Location: chr1:15426014 (GRCh38)
Gene constraint: LOEUF 1.182 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.28 · 5 PDB
Residue 151: an α-helix; the ef-hand 2 domain

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

Similar variants

EFHD2 p.Ala160Val Uncertain significance ★ ⚠ same type
EFHD2 p.Ala161Val Uncertain significance ★ ⚠ same type
EFHD2 p.Ala200Thr Uncertain significance ★ ⚠ same type
EFHD2 p.Ala37Val Uncertain significance ★ ⚠ same type
EFHD2 p.Ala44Val Uncertain significance ★ ⚠ same type
EFHD2 p.Ala45Thr Uncertain significance ★ ⚠ same type
EFHD2 p.Ala51Val Uncertain significance ★ ⚠ same type
EFHD2 p.Arg176Cys 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/efhd2-p-arg151gln (accessed [today's date]).

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