Is DIAPH2 p.Val901Ile (c.2701G>A) pathogenic?

DIAPH2 p.Val901Ile (c.2701G>A) is classified Uncertain significance in DIAPH2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0946); Ultra-rare (popmax 0.0131%, nfe); Associated with premature ovarian failure 2A.

What condition is associated with DIAPH2 p.Val901Ile (c.2701G>A)?

DIAPH2 p.Val901Ile (c.2701G>A) is associated with premature ovarian failure 2A (ClinVar).

How common is DIAPH2 p.Val901Ile (c.2701G>A) in the general population?

DIAPH2 p.Val901Ile (c.2701G>A) is ultra-rare (popmax 0.0131%, nfe) (gnomAD).

What do computational predictors say about DIAPH2 p.Val901Ile (c.2701G>A)?

AlphaMissense predicts likely benign (score 0.0946) — an in-silico prediction, not a clinical call.

DIAPH2 p.Val901Ile

c.2701G>A · rs374934746 · VCV2627063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0946 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

premature ovarian failure 2A

Computational evidence

Protein change
AlphaMissense	0.0946	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -9.10	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 4.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 683 kb · p 0.0098 · regional, not allelic
Overall
CADD	19.23	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 0.0131% European (non-Finnish) · 117/892,477 alleles

Filtering AF 0.0111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0104%

Overall 0.0104% 125/1,202,667 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0131%	7,628
Ashkenazi Jewishnot grpmax-eligible	0.00916%	10,922
African / African-American	0.00526%	19,004
Remaining individualsnot grpmax-eligible	0.00423%	23,659
East Asian	0.00299%	33,450

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: DIAPH2
Protein: p.Val901Ile
Coding: c.2701G>A
MANE Select: NM_006729
dbSNP: rs374934746
Type: single nucleotide variant
Location: chrX:97141776 (GRCh38)
Structure: AlphaFold pLDDT 76.09
Residue 901: the fh2 domain

Full DIAPH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

premature ovarian failure 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DIAPH2 p.Ala83Thr Benign/Likely benign ★★ same condition
DIAPH2 c.733-1G>T Uncertain significance ★ same condition
DIAPH2 p.Asn129Asp Uncertain significance ★ ⚠ same condition
DIAPH2 p.Gln248Lys Uncertain significance ★ ⚠ same condition
DIAPH2 p.Glu529Ala Uncertain significance ⚠ same condition
DIAPH2 p.Ile475= Likely benign ★★ same type
DIAPH2 p.Phe504= Benign ★★ same type
DIAPH2 p.Ala125Val 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/diaph2-p-val901ile (accessed [today's date]).

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