Is DTWD2 p.Pro216Arg (c.647C>G) pathogenic?

DTWD2 p.Pro216Arg (c.647C>G) is classified Uncertain significance in DTWD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: likely pathogenic (0.9645); Absent from gnomAD v4.1.

How common is DTWD2 p.Pro216Arg (c.647C>G) in the general population?

DTWD2 p.Pro216Arg (c.647C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DTWD2 p.Pro216Arg (c.647C>G)?

AlphaMissense predicts likely pathogenic (score 0.9645) — an in-silico prediction, not a clinical call.

DTWD2 p.Pro216Arg

c.647C>G · VCV3505650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9645 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9645	likely pathogenic
REVEL	0.647	pathogenic-leaning
SaProt	LLR -14.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	phastCons 1
Regional constraint	o/e 1.35	unconstrained · MANE · 148 kb · p 8.1e-12 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DTWD2
Protein: p.Pro216Arg
Coding: c.647C>G
MANE Select: NM_173666
Type: single nucleotide variant
Location: chr5:118848169 (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.Pro216Ser 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-pro216arg (accessed [today's date]).

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