Is DMRTA2 p.Pro499Ser (c.1495C>T) pathogenic?

DMRTA2 p.Pro499Ser (c.1495C>T) is classified Uncertain significance in DMRTA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-26). AlphaMissense: ambiguous (0.4685); Very rare (popmax 8.55e-05%, nfe).

How common is DMRTA2 p.Pro499Ser (c.1495C>T) in the general population?

DMRTA2 p.Pro499Ser (c.1495C>T) is very rare (popmax 8.55e-05%, nfe) (gnomAD).

What do computational predictors say about DMRTA2 p.Pro499Ser (c.1495C>T)?

AlphaMissense predicts ambiguous (score 0.4685) — an in-silico prediction, not a clinical call.

DMRTA2 p.Pro499Ser

c.1495C>T · rs2522880311 · VCV3083153

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.55e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4685	ambiguous
REVEL	0.475	indeterminate
SaProt	LLR -6.39	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.99, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 2,497 bp · p 0.091 · regional, not allelic
Overall
CADD	27.0	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 8.55e-05% European (non-Finnish) · 1/1,169,908 alleles

Overall 6.96e-05% 1/1,435,904 alleles · very rare

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: DMRTA2
Protein: p.Pro499Ser
Coding: c.1495C>T
MANE Select: NM_032110
dbSNP: rs2522880311
Type: single nucleotide variant
Location: chr1:50418799 (GRCh38)
Gene constraint: LOEUF 1.236 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.64

Full DMRTA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DMRTA2 p.Leu406Gln Uncertain significance ★★ ⚠ same type
DMRTA2 p.Ala394= Benign ★★ same type
DMRTA2 p.Ala396= Benign ★★ same type
DMRTA2 p.Ser477Asn Benign/Likely benign ★★ ⚠ same type
DMRTA2 p.Ala144Thr Uncertain significance ★ ⚠ same type
DMRTA2 p.Ala14Glu Uncertain significance ★ ⚠ same type
DMRTA2 p.Ala253Pro Uncertain significance ★ ⚠ same type
DMRTA2 p.Ala259Thr 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/dmrta2-p-pro499ser (accessed [today's date]).

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