Is DMRTC2 p.Lys115Arg (c.344A>G) pathogenic?

DMRTC2 p.Lys115Arg (c.344A>G) is classified Uncertain significance in DMRTC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-14). AlphaMissense: likely benign (0.082); Ultra-rare (popmax 0.0201%, nfe).

How common is DMRTC2 p.Lys115Arg (c.344A>G) in the general population?

DMRTC2 p.Lys115Arg (c.344A>G) is ultra-rare (popmax 0.0201%, nfe) (gnomAD).

What do computational predictors say about DMRTC2 p.Lys115Arg (c.344A>G)?

AlphaMissense predicts likely benign (score 0.082) — an in-silico prediction, not a clinical call.

DMRTC2 p.Lys115Arg

c.344A>G · VCV3502743

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.082 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.082	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -5.94	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 5.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 4,264 bp · p 0.055 · regional, not allelic
Overall
CADD	17.23	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0201% European (non-Finnish) · 235/1,167,916 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.0167% 265/1,590,366 alleles · ultra-rare exomes 251/1,438,156 · genomes 14/152,210 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0272%	3,674
European (non-Finnish)grpmax	0.0201%	4,970
Remaining individualsnot grpmax-eligible	0.0146%	6,841
Admixed American	0.00533%	18,759
African / African-American	0.00134%	74,384

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Lys115Arg
Coding: c.344A>G
MANE Select: NM_001040283
Type: single nucleotide variant
Location: chr19:41847855 (GRCh38)
Gene constraint: LOEUF 0.521 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 115: the 'disordered' region

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

Similar variants

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
DMRTC2 p.Ala93Val 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-lys115arg (accessed [today's date]).

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