Is DTWD2 p.Arg246Cys (c.736C>T) pathogenic?

DTWD2 p.Arg246Cys (c.736C>T) is classified Uncertain significance in DTWD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: likely benign (0.1117); Rare (popmax 0.167%, afr).

How common is DTWD2 p.Arg246Cys (c.736C>T) in the general population?

DTWD2 p.Arg246Cys (c.736C>T) is rare (popmax 0.167%, afr) (gnomAD).

What do computational predictors say about DTWD2 p.Arg246Cys (c.736C>T)?

AlphaMissense predicts likely benign (score 0.1117) — an in-silico prediction, not a clinical call.

DTWD2 p.Arg246Cys

c.736C>T · VCV3842777

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1117 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.167%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1117	likely benign
REVEL	0.799	moderately pathogenic-leaning
SaProt	LLR -9.59	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.26	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 6.6	phastCons 1
Regional constraint	o/e 1.35	unconstrained · MANE · 148 kb · p 8.1e-12 · regional, not allelic
Overall
CADD	29.5	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 0.167% African / African-American · 125/74,856 alleles

Filtering AF 0.143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.134%

Overall 0.0145% 234/1,610,612 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.167%	599
Admixed American	0.0586%	1,705
Remaining individualsnot grpmax-eligible	0.0289%	3,464
South Asian	0.0188%	5,331
European (non-Finnish)	0.00323%	31,003
East Asian	0.00224%	44,606

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: DTWD2
Protein: p.Arg246Cys
Coding: c.736C>T
MANE Select: NM_173666
Type: single nucleotide variant
Location: chr5:118841078 (GRCh38)
Gene constraint: LOEUF 1.711 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.75

Full DTWD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DTWD2 p.Arg246His Uncertain significance ★ ⚠ same residue
DTWD2 p.Ala227Thr Uncertain significance ★ ⚠ same type
DTWD2 p.Ala228Pro Uncertain significance ★ ⚠ same type
DTWD2 p.Ala230Thr Uncertain significance ★ ⚠ same type
DTWD2 p.Ala250Asp Uncertain significance ★ ⚠ same type
DTWD2 p.Ala40Val Uncertain significance ★ ⚠ same type
DTWD2 p.Ala42Ser Uncertain significance ★ ⚠ same type
DTWD2 p.Ala7Ser 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/dtwd2-p-arg246cys (accessed [today's date]).

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