Is HAND1 p.Arg91Pro (c.272G>C) pathogenic?

HAND1 p.Arg91Pro (c.272G>C) is classified Uncertain significance in HAND1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely benign (0.2551); Absent from gnomAD v4.1; Associated with hypoplastic left heart syndrome.

What condition is associated with HAND1 p.Arg91Pro (c.272G>C)?

HAND1 p.Arg91Pro (c.272G>C) is associated with hypoplastic left heart syndrome (ClinVar).

How common is HAND1 p.Arg91Pro (c.272G>C) in the general population?

HAND1 p.Arg91Pro (c.272G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HAND1 p.Arg91Pro (c.272G>C)?

AlphaMissense predicts likely benign (score 0.2551) — an in-silico prediction, not a clinical call.

HAND1 p.Arg91Pro

c.272G>C · VCV4699809

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2551 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypoplastic left heart syndrome

Computational evidence

Protein change
AlphaMissense	0.2551	likely benign
REVEL	0.535	indeterminate
SaProt	LLR -6.05	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,199 bp · p 0.97 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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: HAND1
Protein: p.Arg91Pro
Coding: c.272G>C
MANE Select: NM_004821
Type: single nucleotide variant
Location: chr5:154477737 (GRCh38)
Gene constraint: LOEUF 1.188 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.87
Residue 91: the 'disordered' region

Full HAND1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypoplastic left heart syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HAND1 p.Arg91Gly Uncertain significance ★★ ⚠ same residue
HAND1 p.Arg91Ser Uncertain significance ★ same residue
HAND1 p.Ala68Pro Uncertain significance ★★ ⚠ same condition
HAND1 p.Gln43Arg Uncertain significance ★★ ⚠ same condition
HAND1 p.Glu103Gly Uncertain significance ★★ ⚠ same condition
HAND1 p.Gly203Ala Uncertain significance ★★ ⚠ same condition
HAND1 p.Leu3Val Uncertain significance ★★ ⚠ same condition
HAND1 p.Pro125Arg 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/hand1-p-arg91pro (accessed [today's date]).

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