Is EFHC2 p.Pro139= (c.417G>A) pathogenic?

EFHC2 p.Pro139= (c.417G>A) is classified Likely benign in EFHC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-01). Ultra-rare (popmax 0.0447%, nfe).

How common is EFHC2 p.Pro139= (c.417G>A) in the general population?

EFHC2 p.Pro139= (c.417G>A) is ultra-rare (popmax 0.0447%, nfe) (gnomAD).

EFHC2 p.Pro139=

c.417G>A · rs374262479 · VCV2660366

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0447%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.105	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -6.3, phastCons 0.002
Overall
CADD	1.64	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0447% European (non-Finnish) · 396/886,529 alleles

Filtering AF 0.0409% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0395%

Overall 0.0434% 519/1,195,544 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.21%	477
European (non-Finnish)grpmax	0.0447%	2,239
Remaining individualsnot grpmax-eligible	0.0405%	2,468
Ashkenazi Jewishnot grpmax-eligible	0.00927%	10,791
African / African-American	0.00527%	18,984
Admixed American	0.00446%	22,425

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro139=
Coding: c.417G>A
MANE Select: NM_025184
dbSNP: rs374262479
Type: single nucleotide variant
Location: chrX:44261264 (GRCh38)
Structure: AlphaFold pLDDT 79.83 · 4 PDB
Residue 139: the dm10 1 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-pro139 (accessed [today's date]).

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