Is DTNB p.Arg403Cys (c.1207C>T) pathogenic?

DTNB p.Arg403Cys (c.1207C>T) is classified Uncertain significance in DTNB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.3351); Ultra-rare (popmax 0.0254%, afr).

How common is DTNB p.Arg403Cys (c.1207C>T) in the general population?

DTNB p.Arg403Cys (c.1207C>T) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

What do computational predictors say about DTNB p.Arg403Cys (c.1207C>T)?

AlphaMissense predicts likely benign (score 0.3351) — an in-silico prediction, not a clinical call.

DTNB p.Arg403Cys

c.1207C>T · rs369161120 · VCV2481419

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3351 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3351	likely benign
REVEL	0.168	moderately benign-leaning
SaProt	LLR -11.51	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 0.64, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 273 kb · p 0.026 · regional, not allelic
Overall
CADD	29.8	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 0.0254% African / African-American · 19/74,784 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00131% 21/1,607,194 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,936
Remaining individualsnot grpmax-eligible	0.00161%	62,216
European (non-Finnish)	8.5e-05%	1,176,959

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: DTNB
Protein: p.Arg403Cys
Coding: c.1207C>T
MANE Select: NM_021907
dbSNP: rs369161120
Type: single nucleotide variant
Location: chr2:25451598 (GRCh38)
Gene constraint: LOEUF 0.936 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.29
Residue 403: the 'syntrophin-binding region' region

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

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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/dtnb-p-arg403cys (accessed [today's date]).

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