Is DMRT2 p.Arg127Pro (c.380G>C) pathogenic?

DMRT2 p.Arg127Pro (c.380G>C) is classified Uncertain significance in DMRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-29). AlphaMissense: likely pathogenic (0.9988); Absent from gnomAD v4.1; Associated with DMRT2-related disorder.

What condition is associated with DMRT2 p.Arg127Pro (c.380G>C)?

DMRT2 p.Arg127Pro (c.380G>C) is associated with DMRT2-related disorder (ClinVar).

How common is DMRT2 p.Arg127Pro (c.380G>C) in the general population?

DMRT2 p.Arg127Pro (c.380G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DMRT2 p.Arg127Pro (c.380G>C)?

AlphaMissense predicts likely pathogenic (score 0.9988) — an in-silico prediction, not a clinical call.

DMRT2 p.Arg127Pro

c.380G>C · VCV4855004

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9988 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

DMRT2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9988	likely pathogenic · top 4% in DMRT2
REVEL	0.493	indeterminate
SaProt	LLR -16.48	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.42	unconstrained · MANE · 5,656 bp · p 7.1e-31 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DMRT2
Protein: p.Arg127Pro
Coding: c.380G>C
MANE Select: NM_181872
Type: single nucleotide variant
Location: chr9:1051993 (GRCh38)
Gene constraint: LOEUF 1.279 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.37
Residue 127: a DNA-binding region

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

Disease context

DMRT2-related disorder

Similar variants

DMRT2 p.Arg127Ser Uncertain significance ★ ⚠ same residue
DMRT2 p.Ala286Pro Uncertain significance ⚠ same condition
DMRT2 p.Asn247= Likely benign same condition
DMRT2 p.Gly221= Likely benign same condition
DMRT2 p.Ser396Leu Likely benign same condition
DMRT2 p.Ser430= Likely benign same condition
DMRT2 p.Thr557Ala Likely benign same condition
DMRT2 p.Pro41_Ala42insPro Uncertain significance same condition

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-arg127pro (accessed [today's date]).

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