Is DHH p.Ala291Thr (c.871G>A) pathogenic?

DHH p.Ala291Thr (c.871G>A) is classified Uncertain significance in DHH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: likely pathogenic (0.7472); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with DHH p.Ala291Thr (c.871G>A)?

DHH p.Ala291Thr (c.871G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DHH p.Ala291Thr (c.871G>A) in the general population?

DHH p.Ala291Thr (c.871G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DHH p.Ala291Thr (c.871G>A)?

AlphaMissense predicts likely pathogenic (score 0.7472) — an in-silico prediction, not a clinical call.

DHH p.Ala291Thr

c.871G>A · VCV4240003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7472 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7472	likely pathogenic
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -13.38	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 7.5	GERP 2.8, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 4,650 bp · p 8.5e-08 · regional, not allelic
Overall
CADD	27.2	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: DHH
Protein: p.Ala291Thr
Coding: c.871G>A
MANE Select: NM_021044
Type: single nucleotide variant
Location: chr12:49090179 (GRCh38)
Gene constraint: LOEUF 0.999 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.87 · 5 PDB
Residue 291: a UniProt-annotated variant site (in gdmn; uncertain significance); a UniProt-annotated variant site (in gdmn)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DHH p.Arg102His Uncertain significance ★★ ⚠ same condition
DHH p.Ala193Val Uncertain significance ★ ⚠ same condition
DHH p.Ala36Ser Uncertain significance ★ ⚠ same condition
DHH p.Arg102Cys Uncertain significance ★ ⚠ same condition
DHH p.Arg106Gln Uncertain significance ★ ⚠ same condition
DHH p.Arg156Pro Uncertain significance ★ ⚠ same condition
DHH p.Arg179Cys Uncertain significance ★ ⚠ same condition
DHH p.Arg277Pro Uncertain significance ★ ⚠ same condition

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/dhh-p-ala291thr (accessed [today's date]).

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