Is DMRTA2 p.Ser477Arg (c.1431C>A) pathogenic?

DMRTA2 p.Ser477Arg (c.1431C>A) is classified Uncertain significance in DMRTA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely pathogenic (0.9596); Ultra-rare (popmax 0.0126%, amr).

How common is DMRTA2 p.Ser477Arg (c.1431C>A) in the general population?

DMRTA2 p.Ser477Arg (c.1431C>A) is ultra-rare (popmax 0.0126%, amr) (gnomAD).

What do computational predictors say about DMRTA2 p.Ser477Arg (c.1431C>A)?

AlphaMissense predicts likely pathogenic (score 0.9596) — an in-silico prediction, not a clinical call.

DMRTA2 p.Ser477Arg

c.1431C>A · rs765942260 · VCV2225473

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9596 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0126%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9596	likely pathogenic
REVEL	0.162	moderately benign-leaning
SaProt	LLR -7.66	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -0.87, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 2,497 bp · p 0.091 · regional, not allelic
Overall
CADD	15.68	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 0.0126% Admixed American · 6/47,502 alleles

Filtering AF 0.00542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00367%

Overall 0.00101% 14/1,386,294 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0185%	5,419
Admixed Americangrpmax	0.0126%	7,917
Remaining individualsnot grpmax-eligible	0.00338%	29,628
European (non-Finnish)	8.7e-05%	1,149,129

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser477Arg
Coding: c.1431C>A
MANE Select: NM_032110
dbSNP: rs765942260
Type: single nucleotide variant
Location: chr1:50418863 (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.Ser477Asn Benign/Likely benign ★★ ⚠ same residue
DMRTA2 p.Ser477Gly Uncertain significance ★ ⚠ same residue
DMRTA2 p.Leu406Gln Uncertain significance ★★ ⚠ same type
DMRTA2 p.Ala394= Benign ★★ same type
DMRTA2 p.Ala396= Benign ★★ same type
DMRTA2 p.Ala144Thr Uncertain significance ★ ⚠ same type
DMRTA2 p.Ala14Glu Uncertain significance ★ ⚠ same type
DMRTA2 p.Ala253Pro 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-ser477arg (accessed [today's date]).

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