Is DTWD2 p.Thr243Ala (c.727A>G) pathogenic?

DTWD2 p.Thr243Ala (c.727A>G) is classified Uncertain significance in DTWD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: likely benign (0.0841); Rare (popmax 0.164%, nfe).

How common is DTWD2 p.Thr243Ala (c.727A>G) in the general population?

DTWD2 p.Thr243Ala (c.727A>G) is rare (popmax 0.164%, nfe) (gnomAD).

What do computational predictors say about DTWD2 p.Thr243Ala (c.727A>G)?

AlphaMissense predicts likely benign (score 0.0841) — an in-silico prediction, not a clinical call.

DTWD2 p.Thr243Ala

c.727A>G · VCV3842776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0841 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.164%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0841	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -7.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.1	phastCons 1
Regional constraint	o/e 1.35	unconstrained · MANE · 148 kb · p 8.1e-12 · regional, not allelic
Overall
CADD	19.38	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 0.164% European (non-Finnish) · 1,928/1,176,366 alleles

Filtering AF 0.158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.155%

Overall 0.134% 2,158/1,607,192 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.164%	610
Remaining individualsnot grpmax-eligible	0.151%	662
Middle Eastern	0.116%	864
South Asian	0.0655%	1,526
Finnishnot grpmax-eligible	0.0439%	2,278
Admixed American	0.0422%	2,368
African / African-American	0.0214%	4,670
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,484

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.Thr243Ala
Coding: c.727A>G
MANE Select: NM_173666
Type: single nucleotide variant
Location: chr5:118841087 (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.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
DTWD2 p.Arg109Cys 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-thr243ala (accessed [today's date]).

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