Is HAND2 p.Pro97Arg (c.290C>G) pathogenic?

HAND2 p.Pro97Arg (c.290C>G) is classified Uncertain significance in HAND2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-09). AlphaMissense: likely pathogenic (0.6096); Ultra-rare (popmax 0.0167%, amr); Associated with HAND2-related disorder.

What condition is associated with HAND2 p.Pro97Arg (c.290C>G)?

HAND2 p.Pro97Arg (c.290C>G) is associated with HAND2-related disorder (ClinVar).

How common is HAND2 p.Pro97Arg (c.290C>G) in the general population?

HAND2 p.Pro97Arg (c.290C>G) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about HAND2 p.Pro97Arg (c.290C>G)?

AlphaMissense predicts likely pathogenic (score 0.6096) — an in-silico prediction, not a clinical call.

HAND2 p.Pro97Arg

c.290C>G · rs751803965 · VCV2629477

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6096 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

1/2 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	0.6096	likely pathogenic
REVEL	0.478	indeterminate
SaProt	LLR -9.29	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP -1.4, 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

Grpmax group 0.0167% Admixed American · 10/59,754 alleles

Filtering AF 0.00903% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00684%

Overall 0.00472% 76/1,609,850 alleles · ultra-rare exomes 70/1,457,888 · genomes 6/151,962 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,975
East Asian	0.0157%	6,381
European (non-Finnish)	0.00475%	21,041
Remaining individualsnot grpmax-eligible	0.00321%	31,112
South Asian	0.0011%	90,848

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: HAND2
Protein: p.Pro97Arg
Coding: c.290C>G
MANE Select: NM_021973
dbSNP: rs751803965
Type: single nucleotide variant
Location: chr4:173529000 (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-pro97arg (accessed [today's date]).

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