Is DMRT1 p.His135Pro (c.404A>C) pathogenic?

DMRT1 p.His135Pro (c.404A>C) is classified Uncertain significance in DMRT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-15). AlphaMissense: ambiguous (0.48); Very rare (popmax 0.00119%, nfe).

How common is DMRT1 p.His135Pro (c.404A>C) in the general population?

DMRT1 p.His135Pro (c.404A>C) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about DMRT1 p.His135Pro (c.404A>C)?

AlphaMissense predicts ambiguous (score 0.48) — an in-silico prediction, not a clinical call.

DMRT1 p.His135Pro

c.404A>C · rs777256742 · VCV1450329

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.48 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.48	ambiguous
REVEL	0.158	moderately benign-leaning
SaProt	LLR -10.30	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 121 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	26.6	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 0.00119% European (non-Finnish) · 14/1,180,020 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000867% 14/1,613,926 alleles · very rare exomes 11/1,461,844 · genomes 3/152,082 · joint denominator

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: DMRT1
Protein: p.His135Pro
Coding: c.404A>C
MANE Select: NM_021951
dbSNP: rs777256742
Type: single nucleotide variant
Location: chr9:847009 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 57.76 · 1 PDB

Full DMRT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DMRT1 p.His135Gln Uncertain significance ★ ⚠ same residue
DMRT1 p.Asn151Ser Uncertain significance ★★ ⚠ same type
DMRT1 p.Met275Val Uncertain significance ★★ ⚠ same type
DMRT1 p.Ser58Cys Uncertain significance ★★ ⚠ same type
DMRT1 p.Thr366Ser Uncertain significance ★★ ⚠ same type
DMRT1 p.Val265Met Uncertain significance ★★ ⚠ same type
DMRT1 c.355-218G>C Benign ★★ same type
DMRT1 c.355-8G>C Benign ★★ 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/dmrt1-p-his135pro (accessed [today's date]).

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