Is DTWD1 p.Pro85Leu (c.254C>T) pathogenic?

DTWD1 p.Pro85Leu (c.254C>T) is classified Uncertain significance in DTWD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). AlphaMissense: likely pathogenic (0.7917); Rare (popmax 0.135%, amr).

How common is DTWD1 p.Pro85Leu (c.254C>T) in the general population?

DTWD1 p.Pro85Leu (c.254C>T) is rare (popmax 0.135%, amr) (gnomAD).

What do computational predictors say about DTWD1 p.Pro85Leu (c.254C>T)?

AlphaMissense predicts likely pathogenic (score 0.7917) — an in-silico prediction, not a clinical call.

DTWD1 p.Pro85Leu

c.254C>T · rs142654959 · VCV2469729

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7917 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.135%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7917	likely pathogenic
REVEL	0.581	indeterminate
SaProt	LLR -13.72	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 18 kb · p 0.72 · regional, not allelic
Overall
CADD	28.0	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

Grpmax group 0.135% Admixed American · 80/59,472 alleles

Filtering AF 0.111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.105%

Overall 0.0919% 1,479/1,609,206 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.135%	743
European (non-Finnish)	0.112%	893
Remaining individualsnot grpmax-eligible	0.0914%	1,094
South Asian	0.0156%	6,426
African / African-American	0.00801%	12,479
Finnishnot grpmax-eligible	0.00469%	21,325

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: DTWD1
Protein: p.Pro85Leu
Coding: c.254C>T
MANE Select: NM_001144955
dbSNP: rs142654959
Type: single nucleotide variant
Location: chr15:49625421 (GRCh38)
Gene constraint: LOEUF 1.283 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.50

Full DTWD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DTWD1 p.Ala31Ser Uncertain significance ★ ⚠ same type
DTWD1 p.Arg178Cys Uncertain significance ★ ⚠ same type
DTWD1 p.Arg178His Uncertain significance ★ ⚠ same type
DTWD1 p.Arg238His Uncertain significance ★ ⚠ same type
DTWD1 p.Asn210Ser Uncertain significance ★ ⚠ same type
DTWD1 p.Asn78His Uncertain significance ★ ⚠ same type
DTWD1 p.Asp188Val Uncertain significance ★ ⚠ same type
DTWD1 p.Asp275Asn 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/dtwd1-p-pro85leu (accessed [today's date]).

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