Is DMTF1 p.Arg446Cys (c.1336C>T) pathogenic?

DMTF1 p.Arg446Cys (c.1336C>T) is classified Uncertain significance in DMTF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). AlphaMissense: likely benign (0.1455); Ultra-rare (popmax 0.0401%, eas).

How common is DMTF1 p.Arg446Cys (c.1336C>T) in the general population?

DMTF1 p.Arg446Cys (c.1336C>T) is ultra-rare (popmax 0.0401%, eas) (gnomAD).

What do computational predictors say about DMTF1 p.Arg446Cys (c.1336C>T)?

AlphaMissense predicts likely benign (score 0.1455) — an in-silico prediction, not a clinical call.

DMTF1 p.Arg446Cys

c.1336C>T · VCV4012355

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1455 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1455	likely benign
REVEL	0.212	benign-leaning
SaProt	LLR -8.18	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 4.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 7,032 bp · p 0.62 · regional, not allelic
Overall
CADD	26.5	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 0.0401% East Asian · 18/44,874 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00304% 49/1,613,904 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0401%	2,493
African / African-American	0.008%	12,498
European (non-Finnish)	0.00186%	53,632
Admixed American	0.00167%	59,972
Finnishnot grpmax-eligible	0.00156%	64,024
South Asian	0.0011%	91,084

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: DMTF1
Protein: p.Arg446Cys
Coding: c.1336C>T
MANE Select: NM_001142327
Type: single nucleotide variant
Location: chr7:87188226 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI 0.72 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 1 PDB
Residue 446: the 'required for dna-binding' region; the 'interaction with ccnd1, ccnd2 and ccnd3' region

Full DMTF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DMP1 p.Glu446Lys Uncertain significance ★ ⚠ same residue
DMP1 p.Gly135Ter Pathogenic/Likely pathogenic ★★ same type
DMP1 p.Met1Val Pathogenic/Likely pathogenic ★★ same type
DMP1 c.*159T>A Uncertain significance ★★ same type
DMP1 c.*77T>C Uncertain significance ★★ same type
DMP1 p.Arg173Trp Uncertain significance ★★ ⚠ same type
DMP1 p.Arg302Ile Uncertain significance ★★ ⚠ same type
DMP1 p.Arg310Lys 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/dmtf1-p-arg446cys (accessed [today's date]).

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