Is DNTT p.Arg442Cys (c.1324C>T) pathogenic?

DNTT p.Arg442Cys (c.1324C>T) is classified Uncertain significance in DNTT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.1323); Ultra-rare (popmax 0.02%, eas).

How common is DNTT p.Arg442Cys (c.1324C>T) in the general population?

DNTT p.Arg442Cys (c.1324C>T) is ultra-rare (popmax 0.02%, eas) (gnomAD).

What do computational predictors say about DNTT p.Arg442Cys (c.1324C>T)?

AlphaMissense predicts likely benign (score 0.1323) — an in-silico prediction, not a clinical call.

DNTT p.Arg442Cys

c.1324C>T · VCV4013982

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1323 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1323	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -8.96	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 1.8	GERP 1.6, phastCons 0.11
Regional constraint	o/e 1.06	unconstrained · MANE · 34 kb · p 0.13 · regional, not allelic
Overall
CADD	21.6	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 0.02% East Asian · 9/44,894 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00167% 27/1,613,992 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.02%	4,988
Admixed American	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0032%	31,242
Finnishnot grpmax-eligible	0.00156%	64,034
South Asian	0.0011%	91,074
European (non-Finnish)	0.000847%	117,999

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: DNTT
Protein: p.Arg442Cys
Coding: c.1324C>T
MANE Select: NM_004088
Type: single nucleotide variant
Location: chr10:96332561 (GRCh38)
Gene constraint: LOEUF 0.942 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.49 · 2 PDB
Residue 442: the 'mediates interaction with dnttip2' region

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

Similar variants

DNTT p.Arg442Leu Uncertain significance ★ ⚠ same residue
DNTT c.203+7C>G Benign ★★ same type
DNTT c.203+9G>A Benign ★★ same type
DNTT p.Ala90Val Benign ★★ same type
DNTT p.Asp280His Likely benign ★★ ⚠ same type
DNTT p.Glu244= Benign/Likely benign ★★ same type
DNTT p.Ala194Val Uncertain significance ★ ⚠ same type
DNTT p.Ala195Thr 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/dntt-p-arg442cys (accessed [today's date]).

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