Is HAND1 p.Pro61= (c.183G>A) pathogenic?

HAND1 p.Pro61= (c.183G>A) is classified Likely benign in HAND1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-21). Ultra-rare (popmax 0.0136%, amr); Associated with hypoplastic left heart syndrome.

What condition is associated with HAND1 p.Pro61= (c.183G>A)?

HAND1 p.Pro61= (c.183G>A) is associated with hypoplastic left heart syndrome (ClinVar).

How common is HAND1 p.Pro61= (c.183G>A) in the general population?

HAND1 p.Pro61= (c.183G>A) is ultra-rare (popmax 0.0136%, amr) (gnomAD).

HAND1 p.Pro61=

c.183G>A · rs774965575 · VCV1604176

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, amr)

Conditions

hypoplastic left heart syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -4.1
Overall
CADD	9.456	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0136% Admixed American · 8/58,894 alleles

Filtering AF 0.00672% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0049%

Overall 0.000566% 9/1,590,226 alleles · ultra-rare exomes 7/1,441,036 · genomes 2/149,190 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0136%	7,362
European (non-Finnish)	8.51e-05%	1,175,508

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: HAND1
Protein: p.Pro61=
Coding: c.183G>A
MANE Select: NM_004821
dbSNP: rs774965575
Type: single nucleotide variant
Location: chr5:154477826 (GRCh38)
Gene constraint: LOEUF 1.188 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.87
Residue 61: 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.Pro61Gln Uncertain significance ★ ⚠ same residue
HAND1 p.Pro61Ser Uncertain significance ★ ⚠ same residue
HAND1 p.Ala68Pro Uncertain significance ★★ ⚠ same condition
HAND1 p.Arg91Gly 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

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-pro61 (accessed [today's date]).

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