Is DTWD2 p.Ile174Val (c.520A>G) pathogenic?

DTWD2 p.Ile174Val (c.520A>G) is classified Uncertain significance in DTWD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.0738); Ultra-rare (popmax 0.0967%, eas).

How common is DTWD2 p.Ile174Val (c.520A>G) in the general population?

DTWD2 p.Ile174Val (c.520A>G) is ultra-rare (popmax 0.0967%, eas) (gnomAD).

What do computational predictors say about DTWD2 p.Ile174Val (c.520A>G)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

DTWD2 p.Ile174Val

c.520A>G · rs200186053 · VCV2344229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0967%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -7.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.48	acceptor gain · deltas
Pangolin	Δ0.32	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.014	GERP 2.5, phastCons 0.92
Regional constraint	o/e 1.35	unconstrained · MANE · 148 kb · p 8.1e-12 · regional, not allelic
Overall
CADD	19.55	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 0.0967% East Asian · 43/44,458 alleles

Filtering AF 0.0737% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0656%

Overall 0.0114% 182/1,602,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0967%	1,034
Admixed American	0.0672%	1,489
African / African-American	0.0441%	2,267
Remaining individualsnot grpmax-eligible	0.0161%	6,193
South Asian	0.0125%	7,987
European (non-Finnish)	0.00375%	26,678
Finnishnot grpmax-eligible	0.00158%	63,398

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.Ile174Val
Coding: c.520A>G
MANE Select: NM_173666
dbSNP: rs200186053
Type: single nucleotide variant
Location: chr5:118928614 (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-ile174val (accessed [today's date]).

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