Is DMRTC2 p.Arg59His (c.176G>A) pathogenic?

DMRTC2 p.Arg59His (c.176G>A) is classified Uncertain significance in DMRTC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-07). AlphaMissense: likely benign (0.1624); Very rare (popmax 0.00161%, nfe).

How common is DMRTC2 p.Arg59His (c.176G>A) in the general population?

DMRTC2 p.Arg59His (c.176G>A) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about DMRTC2 p.Arg59His (c.176G>A)?

AlphaMissense predicts likely benign (score 0.1624) — an in-silico prediction, not a clinical call.

DMRTC2 p.Arg59His

c.176G>A · VCV3502742

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1624 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1624	likely benign
REVEL	0.553	indeterminate
SaProt	LLR -10.58	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 0.88, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 4,264 bp · p 0.055 · regional, not allelic
Overall
CADD	19.16	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 0.00161% European (non-Finnish) · 19/1,180,052 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00124% 20/1,614,068 alleles · very rare exomes 19/1,461,880 · genomes 1/152,188 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,108
South Asian	0.0011%	91,082

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: DMRTC2
Protein: p.Arg59His
Coding: c.176G>A
MANE Select: NM_001040283
Type: single nucleotide variant
Location: chr19:41847604 (GRCh38)
Gene constraint: LOEUF 0.521 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 59: a DNA-binding region

Full DMRTC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DMRTC2 p.Arg59Cys Uncertain significance ★ same residue
DMRTC2 p.Ala202Thr Uncertain significance ★ ⚠ same type
DMRTC2 p.Ala280Val Uncertain significance ★ ⚠ same type
DMRTC2 p.Ala295Thr Uncertain significance ★ ⚠ same type
DMRTC2 p.Ala307Ser Uncertain significance ★ ⚠ same type
DMRTC2 p.Ala350Val Uncertain significance ★ ⚠ same type
DMRTC2 p.Ala35Val Uncertain significance ★ ⚠ same type
DMRTC2 p.Ala65Ser 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/dmrtc2-p-arg59his (accessed [today's date]).

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