Is DMRT3 p.Ala225Val (c.674C>T) pathogenic?

DMRT3 p.Ala225Val (c.674C>T) is classified Likely benign in DMRT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-17). AlphaMissense: likely benign (0.0755); Ultra-rare (popmax 0.0164%, mid).

How common is DMRT3 p.Ala225Val (c.674C>T) in the general population?

DMRT3 p.Ala225Val (c.674C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about DMRT3 p.Ala225Val (c.674C>T)?

AlphaMissense predicts likely benign (score 0.0755) — an in-silico prediction, not a clinical call.

DMRT3 p.Ala225Val

c.674C>T · rs752903154 · VCV2341563

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0755 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0755	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -6.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -1.5, phastCons 0.18
Regional constraint	o/e 1.23	unconstrained · MANE · 14 kb · p 1.2e-08 · regional, not allelic
Overall
CADD	0.087	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00273% 44/1,613,772 alleles · ultra-rare exomes 36/1,461,796 · genomes 8/151,976 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.01%	9,998
South Asian	0.00549%	18,208
African / African-American	0.00401%	24,950
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.00212%	47,201
Finnishnot grpmax-eligible	0.00156%	63,910

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.Ala225Val
Coding: c.674C>T
MANE Select: NM_021240
dbSNP: rs752903154
Type: single nucleotide variant
Location: chr9:990260 (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-ala225val (accessed [today's date]).

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