Is DMRT3 p.Ile59Ser (c.176T>G) pathogenic?

DMRT3 p.Ile59Ser (c.176T>G) is classified Uncertain significance in DMRT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: likely pathogenic (0.9784); Very rare (popmax 0.0067%, eas).

How common is DMRT3 p.Ile59Ser (c.176T>G) in the general population?

DMRT3 p.Ile59Ser (c.176T>G) is very rare (popmax 0.0067%, eas) (gnomAD).

What do computational predictors say about DMRT3 p.Ile59Ser (c.176T>G)?

AlphaMissense predicts likely pathogenic (score 0.9784) — an in-silico prediction, not a clinical call.

DMRT3 p.Ile59Ser

c.176T>G · rs1233365158 · VCV3083130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9784 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0067%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9784	likely pathogenic
REVEL	0.274	benign-leaning
SaProt	LLR -6.59	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 3.2	GERP -4.6, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 14 kb · p 1.2e-08 · regional, not allelic
Overall
CADD	25.3	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 0.0067% East Asian · 3/44,750 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000893%

Overall 0.000248% 4/1,610,508 alleles · very rare exomes 4/1,458,336 · genomes 0/152,172 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0067%	14,917
European (non-Finnish)	8.48e-05%	1,178,738

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.Ile59Ser
Coding: c.176T>G
MANE Select: NM_021240
dbSNP: rs1233365158
Type: single nucleotide variant
Location: chr9:977177 (GRCh38)
Gene constraint: LOEUF 1.273 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.72
Residue 59: a DNA-binding region

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-ile59ser (accessed [today's date]).

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