Is HAND2 p.Val129Ile (c.385G>A) pathogenic?

HAND2 p.Val129Ile (c.385G>A) is classified Uncertain significance in HAND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-02). AlphaMissense: likely pathogenic (0.9246); Absent from gnomAD v4.1; Associated with HAND2-related disorder.

What condition is associated with HAND2 p.Val129Ile (c.385G>A)?

HAND2 p.Val129Ile (c.385G>A) is associated with HAND2-related disorder (ClinVar).

How common is HAND2 p.Val129Ile (c.385G>A) in the general population?

HAND2 p.Val129Ile (c.385G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HAND2 p.Val129Ile (c.385G>A)?

AlphaMissense predicts likely pathogenic (score 0.9246) — an in-silico prediction, not a clinical call.

HAND2 p.Val129Ile

c.385G>A · rs199503638 · VCV2633648

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9246 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

HAND2-related disorder

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.9246	likely pathogenic
REVEL	0.483	indeterminate
SaProt	LLR -11.52	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 0.96, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 163 bp · p 6.4e-07 · regional, not allelic
Overall
CADD	34.0	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

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.Val129Ile
Coding: c.385G>A
MANE Select: NM_021973
dbSNP: rs199503638
Type: single nucleotide variant
Location: chr4:173528905 (GRCh38)

Full HAND2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

HAND2-related disorder

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-val129ile (accessed [today's date]).

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