Is DMRT2 p.Ala422Val (c.1265C>T) pathogenic?

DMRT2 p.Ala422Val (c.1265C>T) is classified Uncertain significance in DMRT2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-30). AlphaMissense: likely benign (0.0701); Rare (popmax 0.341%, sas).

How common is DMRT2 p.Ala422Val (c.1265C>T) in the general population?

DMRT2 p.Ala422Val (c.1265C>T) is rare (popmax 0.341%, sas) (gnomAD).

What do computational predictors say about DMRT2 p.Ala422Val (c.1265C>T)?

AlphaMissense predicts likely benign (score 0.0701) — an in-silico prediction, not a clinical call.

DMRT2 p.Ala422Val

c.1265C>T · rs143092642 · VCV3043138

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0701 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.341%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0701	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -6.47	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 1.1	GERP 1.2, phastCons 0.59
Regional constraint	o/e 1.42	unconstrained · MANE · 5,656 bp · p 7.1e-31 · regional, not allelic
Overall
CADD	13.25	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 0.341% South Asian · 311/91,078 alleles

Filtering AF 0.31% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.298%

Overall 0.13% 2,102/1,614,154 alleles · rare exomes 1,974/1,461,878 · genomes 128/152,276 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.341%	293
Ashkenazi Jewishnot grpmax-eligible	0.236%	423
European (non-Finnish)	0.134%	748
Middle Eastern	0.115%	866
Remaining individualsnot grpmax-eligible	0.102%	977
Admixed American	0.0733%	1,364
African / African-American	0.032%	3,127
Finnishnot grpmax-eligible	0.00469%	21,339
East Asian	0.00223%	44,868

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: DMRT2
Protein: p.Ala422Val
Coding: c.1265C>T
MANE Select: NM_181872
dbSNP: rs143092642
Type: single nucleotide variant
Location: chr9:1056852 (GRCh38)
Gene constraint: LOEUF 1.279 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.37
Residue 422: the 'disordered' region

Full DMRT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DMRT2 p.Ala112Glu Uncertain significance ★★ ⚠ same type
DMRT2 p.Ala29Ser Uncertain significance ★★ ⚠ same type
DMRT2 p.Asp176Gly Uncertain significance ★★ ⚠ same type
DMRT2 p.Asp48Glu Uncertain significance ★★ ⚠ same type
DMRT2 p.Cys105Tyr Uncertain significance ★★ ⚠ same type
DMRT2 p.Glu60Gln Uncertain significance ★★ ⚠ same type
DMRT2 p.Gly110Asp Uncertain significance ★★ ⚠ same type
DMRT2 p.Gly36Arg 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/dmrt2-p-ala422val (accessed [today's date]).

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