Is DTWD2 p.Ala230Thr (c.688G>A) pathogenic?

DTWD2 p.Ala230Thr (c.688G>A) is classified Uncertain significance in DTWD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: likely benign (0.1486); Rare (popmax 0.124%, amr).

How common is DTWD2 p.Ala230Thr (c.688G>A) in the general population?

DTWD2 p.Ala230Thr (c.688G>A) is rare (popmax 0.124%, amr) (gnomAD).

What do computational predictors say about DTWD2 p.Ala230Thr (c.688G>A)?

AlphaMissense predicts likely benign (score 0.1486) — an in-silico prediction, not a clinical call.

DTWD2 p.Ala230Thr

c.688G>A · rs148574499 · VCV2265693

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1486 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.124%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1486	likely benign
REVEL	0.619	indeterminate
SaProt	LLR -8.95	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	phastCons 1
Regional constraint	o/e 1.35	unconstrained · MANE · 148 kb · p 8.1e-12 · regional, not allelic
Overall
CADD	23.6	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 0.124% Admixed American · 70/56,262 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0989%

Overall 0.0879% 1,396/1,588,242 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.124%	804
European (non-Finnish)	0.106%	945
Remaining individualsnot grpmax-eligible	0.0832%	1,202
Middle Eastern	0.0334%	2,994
African / African-American	0.0299%	3,349
Finnishnot grpmax-eligible	0.0205%	4,878
Ashkenazi Jewishnot grpmax-eligible	0.00345%	28,976

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.Ala230Thr
Coding: c.688G>A
MANE Select: NM_173666
dbSNP: rs148574499
Type: single nucleotide variant
Location: chr5:118848128 (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.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
DTWD2 p.Arg109His 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-ala230thr (accessed [today's date]).

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