Is DMRT3 p.Ser85Arg (c.253A>C) pathogenic?

DMRT3 p.Ser85Arg (c.253A>C) is classified Uncertain significance in DMRT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely pathogenic (0.9438); Rare (popmax 0.18%, afr).

How common is DMRT3 p.Ser85Arg (c.253A>C) in the general population?

DMRT3 p.Ser85Arg (c.253A>C) is rare (popmax 0.18%, afr) (gnomAD).

What do computational predictors say about DMRT3 p.Ser85Arg (c.253A>C)?

AlphaMissense predicts likely pathogenic (score 0.9438) — an in-silico prediction, not a clinical call.

DMRT3 p.Ser85Arg

c.253A>C · VCV4660554

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9438 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.18%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9438	likely pathogenic
REVEL	0.067	moderately benign-leaning
SaProt	LLR -6.42	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 8.8	GERP -3, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 14 kb · p 1.2e-08 · regional, not allelic
Overall
CADD	24.6	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 0.18% African / African-American · 130/72,386 alleles

Filtering AF 0.154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.145%

Overall 0.0101% 159/1,580,576 alleles · rare exomes 70/1,429,138 · genomes 89/151,438 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.18%	557
Middle Eastern	0.0172%	5,812
Admixed American	0.0156%	6,412
Remaining individualsnot grpmax-eligible	0.0148%	6,757
European (non-Finnish)	0.00086%	116,252

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: DMRT3
Protein: p.Ser85Arg
Coding: c.253A>C
MANE Select: NM_021240
Type: single nucleotide variant
Location: chr9:977254 (GRCh38)
Gene constraint: LOEUF 1.273 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.72

Full DMRT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DMRT3 p.Arg217Cys Likely benign ★★ same type
DMRT3 p.Asn261Thr Benign ★★ same type
DMRT3 p.Pro18Gln Benign ★★ same type
DMRT3 p.Pro98= Benign ★★ same type
DMRT3 p.Ser463Pro Benign ★★ same type
DMRT3 p.Val424Ile Likely benign ★★ same type
DMRT3 p.Pro443Ser Likely pathogenic ★ ⚠ same type
DMRT3 p.Ala103Thr 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/dmrt3-p-ser85arg (accessed [today's date]).

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