Is EFHC2 p.Pro412Leu (c.1235C>T) pathogenic?

EFHC2 p.Pro412Leu (c.1235C>T) is classified Uncertain significance in EFHC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: likely benign (0.1596); Very rare (popmax 0.00537%, nfe).

How common is EFHC2 p.Pro412Leu (c.1235C>T) in the general population?

EFHC2 p.Pro412Leu (c.1235C>T) is very rare (popmax 0.00537%, nfe) (gnomAD).

What do computational predictors say about EFHC2 p.Pro412Leu (c.1235C>T)?

AlphaMissense predicts likely benign (score 0.1596) — an in-silico prediction, not a clinical call.

EFHC2 p.Pro412Leu

c.1235C>T · rs777095426 · VCV2488697

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1596 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00537%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1596	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -10.15	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 5.7	GERP 3.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 195 kb · p 0.037 · regional, not allelic
Overall
CADD	14.18	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 0.00537% European (non-Finnish) · 48/893,239 alleles

Filtering AF 0.00416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00368%

Overall 0.00415% 50/1,205,419 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00537%	18,609
Admixed American	0.00221%	45,226
African / African-American	0.00176%	56,980

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.Pro412Leu
Coding: c.1235C>T
MANE Select: NM_025184
dbSNP: rs777095426
Type: single nucleotide variant
Location: chrX:44242166 (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.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-pro412leu (accessed [today's date]).

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