Is EFHD1 p.Pro40His (c.119C>A) pathogenic?

EFHD1 p.Pro40His (c.119C>A) is classified Uncertain significance in EFHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely benign (0.1053); Rare (popmax 0.223%, afr).

How common is EFHD1 p.Pro40His (c.119C>A) in the general population?

EFHD1 p.Pro40His (c.119C>A) is rare (popmax 0.223%, afr) (gnomAD).

What do computational predictors say about EFHD1 p.Pro40His (c.119C>A)?

AlphaMissense predicts likely benign (score 0.1053) — an in-silico prediction, not a clinical call.

EFHD1 p.Pro40His

c.119C>A · rs991080128 · VCV2375416

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1053 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.223%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1053	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -12.52	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -0.098, phastCons 0.041
Regional constraint	o/e 0.95	unconstrained · MANE · 48 kb · p 0.33 · regional, not allelic
Overall
CADD	15.31	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 0.223% African / African-American · 151/67,756 alleles

Filtering AF 0.194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.183%

Overall 0.0111% 164/1,475,458 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.223%	449
Remaining individualsnot grpmax-eligible	0.014%	7,135
Admixed American	0.00715%	13,991
European (non-Finnish)	0.000178%	561,344

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: EFHD1
Protein: p.Pro40His
Coding: c.119C>A
MANE Select: NM_025202
dbSNP: rs991080128
Type: single nucleotide variant
Location: chr2:232633823 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.10
Residue 40: the 'disordered' region

Full EFHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFHD1 p.Ala124Thr Uncertain significance ★ ⚠ same type
EFHD1 p.Ala159Val Uncertain significance ★ ⚠ same type
EFHD1 p.Ala19Asp Uncertain significance ★ ⚠ same type
EFHD1 p.Ala49Pro Uncertain significance ★ ⚠ same type
EFHD1 p.Arg13Trp Uncertain significance ★ ⚠ same type
EFHD1 p.Arg149Gln Uncertain significance ★ ⚠ same type
EFHD1 p.Arg218Trp Uncertain significance ★ ⚠ same type
EFHD1 p.Arg224Gly 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/efhd1-p-pro40his (accessed [today's date]).

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