Is DTWD2 p.Pro216Ser (c.646C>T) pathogenic?

DTWD2 p.Pro216Ser (c.646C>T) is classified Uncertain significance in DTWD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-06). AlphaMissense: likely pathogenic (0.9838); Rare (popmax 0.198%, mid).

How common is DTWD2 p.Pro216Ser (c.646C>T) in the general population?

DTWD2 p.Pro216Ser (c.646C>T) is rare (popmax 0.198%, mid) (gnomAD).

What do computational predictors say about DTWD2 p.Pro216Ser (c.646C>T)?

AlphaMissense predicts likely pathogenic (score 0.9838) — an in-silico prediction, not a clinical call.

DTWD2 p.Pro216Ser

c.646C>T · rs183646069 · VCV3086098

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9838 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.198%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9838	likely pathogenic · top 9% in DTWD2
REVEL	0.669	pathogenic-leaning
SaProt	LLR -12.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 1.35	unconstrained · MANE · 148 kb · p 8.1e-12 · regional, not allelic
Overall
CADD	25.3	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

Grpmax group 0.198% Middle Eastern · 12/6,046 alleles

Filtering AF 0.114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0897%

Overall 0.0143% 229/1,606,384 alleles · rare exomes 196/1,454,122 · genomes 33/152,262 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.198%	504
Admixed American	0.0781%	1,280
Remaining individualsnot grpmax-eligible	0.0434%	2,302
European (non-Finnish)	0.0114%	8,781
African / African-American	0.0107%	9,335
Finnishnot grpmax-eligible	0.00313%	31,922

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.Pro216Ser
Coding: c.646C>T
MANE Select: NM_173666
dbSNP: rs183646069
Type: single nucleotide variant
Location: chr5:118848170 (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.Pro216Arg 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-pro216ser (accessed [today's date]).

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