Is DMRT2 p.Pro40Gln (c.119C>A) pathogenic?

DMRT2 p.Pro40Gln (c.119C>A) is classified Uncertain significance in DMRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: likely benign (0.0757); Very rare (popmax 0.00119%, sas).

How common is DMRT2 p.Pro40Gln (c.119C>A) in the general population?

DMRT2 p.Pro40Gln (c.119C>A) is very rare (popmax 0.00119%, sas) (gnomAD).

What do computational predictors say about DMRT2 p.Pro40Gln (c.119C>A)?

AlphaMissense predicts likely benign (score 0.0757) — an in-silico prediction, not a clinical call.

DMRT2 p.Pro40Gln

c.119C>A · VCV4012300

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0757 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0757	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -10.80	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 0.42	GERP -0.24, phastCons 0.03
Regional constraint	o/e 1.42	unconstrained · MANE · 5,656 bp · p 7.1e-31 · regional, not allelic
Overall
CADD	15.95	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 0.00119% South Asian · 1/83,700 alleles

Overall 6.52e-05% 1/1,533,858 alleles · very rare exomes 1/1,381,898 · genomes 0/151,960 · joint denominator

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.Pro40Gln
Coding: c.119C>A
MANE Select: NM_181872
Type: single nucleotide variant
Location: chr9:1051732 (GRCh38)
Gene constraint: LOEUF 1.279 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.37
Residue 40: the 'disordered' region

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

Similar variants

DMRT2 p.Pro40Leu Uncertain significance ★ ⚠ same residue
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

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-pro40gln (accessed [today's date]).

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