Is DMTN p.Arg325Ser (c.975G>T) pathogenic?

DMTN p.Arg325Ser (c.975G>T) is classified Uncertain significance in DMTN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-29). AlphaMissense: ambiguous (0.3774); Ultra-rare (popmax 0.0168%, amr).

How common is DMTN p.Arg325Ser (c.975G>T) in the general population?

DMTN p.Arg325Ser (c.975G>T) is ultra-rare (popmax 0.0168%, amr) (gnomAD).

What do computational predictors say about DMTN p.Arg325Ser (c.975G>T)?

AlphaMissense predicts ambiguous (score 0.3774) — an in-silico prediction, not a clinical call.

DMTN p.Arg325Ser

c.975G>T · rs571082795 · VCV2224588

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3774 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3774	ambiguous
REVEL	0.049	moderately benign-leaning
SaProt	LLR -6.48	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 15 kb · p 0.0007 · regional, not allelic
Overall
CADD	21.8	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 0.0168% Admixed American · 10/59,660 alleles

Filtering AF 0.00905% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00685%

Overall 0.00193% 31/1,602,136 alleles · ultra-rare exomes 27/1,449,786 · genomes 4/152,350 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0168%	5,966
South Asian	0.01%	9,997
Remaining individualsnot grpmax-eligible	0.00323%	30,937
East Asian	0.00224%	44,554
European (non-Finnish)	0.000768%	130,240

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: DMTN
Protein: p.Arg325Ser
Coding: c.975G>T
MANE Select: NM_001387751
dbSNP: rs571082795
Type: single nucleotide variant
Location: chr8:22080822 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.03 · 2 PDB
Residue 325: the 'disordered' region

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

Similar variants

DMTN c.295-2A>T Uncertain significance ★ same type
DMTN c.604+2T>G Uncertain significance ★ same type
DMTN p.Ala199Gly Uncertain significance ★ ⚠ same type
DMTN p.Arg135Cys Uncertain significance ★ ⚠ same type
DMTN p.Arg150Lys Uncertain significance ★ ⚠ same type
DMTN p.Arg208Trp Uncertain significance ★ ⚠ same type
DMTN p.Arg212Trp Uncertain significance ★ ⚠ same type
DMTN p.Arg236Leu 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/dmtn-p-arg325ser (accessed [today's date]).

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