Is HAND2 p.Asp76Ala (c.227A>C) pathogenic?

HAND2 p.Asp76Ala (c.227A>C) is classified Uncertain significance in HAND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-29). AlphaMissense: ambiguous (0.4626); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with HAND2 p.Asp76Ala (c.227A>C)?

HAND2 p.Asp76Ala (c.227A>C) is associated with Inborn genetic diseases (ClinVar).

How common is HAND2 p.Asp76Ala (c.227A>C) in the general population?

HAND2 p.Asp76Ala (c.227A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HAND2 p.Asp76Ala (c.227A>C)?

AlphaMissense predicts ambiguous (score 0.4626) — an in-silico prediction, not a clinical call.

HAND2 p.Asp76Ala

c.227A>C · VCV3856732

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4626 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4626	ambiguous
REVEL	0.505	indeterminate
SaProt	LLR -5.38	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP -3.1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 300 bp · p 0.15 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

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: HAND2
Protein: p.Asp76Ala
Coding: c.227A>C
MANE Select: NM_021973
Type: single nucleotide variant
Location: chr4:173529063 (GRCh38)
Gene constraint: LOEUF 0.601 · pLI 0.89 (gnomAD)
Structure: AlphaFold pLDDT 67.30
Residue 76: the 'disordered' region

Full HAND2 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

HAND2 p.Gly162Ser Uncertain significance ★★ ⚠ same condition
HAND2 p.Gly74Ser Uncertain significance ★★ ⚠ same condition
HAND2 p.Lys216Asn Uncertain significance ★★ ⚠ same condition
HAND2 p.Ala21Gly Uncertain significance ★ ⚠ same condition
HAND2 p.Ala21Ser Uncertain significance ★ ⚠ same condition
HAND2 p.Ala23Val Uncertain significance ★ same condition
HAND2 p.Ala69Asp Conflicting classifications of pathogenicity ★ same condition
HAND2 p.Ala72Thr 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/hand2-p-asp76ala (accessed [today's date]).

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