Is DTHD1 p.Pro841Ala (c.2521C>G) pathogenic?

DTHD1 p.Pro841Ala (c.2521C>G) is classified Uncertain significance in DTHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-22). AlphaMissense: likely benign (0.1566); Absent from gnomAD v4.1.

How common is DTHD1 p.Pro841Ala (c.2521C>G) in the general population?

DTHD1 p.Pro841Ala (c.2521C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DTHD1 p.Pro841Ala (c.2521C>G)?

AlphaMissense predicts likely benign (score 0.1566) — an in-silico prediction, not a clinical call.

DTHD1 p.Pro841Ala

c.2521C>G · VCV3675657

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1566 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1566	likely benign
REVEL	0.688	pathogenic-leaning
SaProt	LLR -8.43	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.99	unconstrained · MANE · 62 kb · p 0.66 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P716A vs ClinVar P841A) — verify the residue.

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: DTHD1
Protein: p.Pro841Ala
Coding: c.2521C>G
MANE Select: NM_001170700
Type: single nucleotide variant
Location: chr4:36343624 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.99
Residue 716 UniProt numbering: the death domain

Full DTHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DTHD1 c.1218+1G>A Uncertain significance ★★ same type
DTHD1 c.1219-2A>G Uncertain significance ★★ same type
DTHD1 p.Ala552Ser Uncertain significance ★★ ⚠ same type
DTHD1 p.Ala811Asp Uncertain significance ★★ ⚠ same type
DTHD1 p.Arg326Gln Uncertain significance ★★ ⚠ same type
DTHD1 p.Arg371Cys Uncertain significance ★★ ⚠ same type
DTHD1 p.Arg447Gln Uncertain significance ★★ ⚠ same type
DTHD1 p.Arg447Ter 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/dthd1-p-pro841ala (accessed [today's date]).

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