Is HAND1 p.Pro49= (c.147G>C) pathogenic?

HAND1 p.Pro49= (c.147G>C) is classified Likely benign in HAND1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-14). Ultra-rare (popmax 0.0134%, afr); Associated with hypoplastic left heart syndrome.

What condition is associated with HAND1 p.Pro49= (c.147G>C)?

HAND1 p.Pro49= (c.147G>C) is associated with hypoplastic left heart syndrome (ClinVar).

How common is HAND1 p.Pro49= (c.147G>C) in the general population?

HAND1 p.Pro49= (c.147G>C) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

HAND1 p.Pro49=

c.147G>C · VCV3702840

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

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 -5.3	GERP -3.9
Overall
CADD	5.906	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% African / African-American · 10/74,904 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.000624% 10/1,601,692 alleles · ultra-rare exomes 6/1,449,516 · genomes 4/152,176 · joint denominator

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.Pro49=
Coding: c.147G>C
MANE Select: NM_004821
Type: single nucleotide variant
Location: chr5:154477862 (GRCh38)
Gene constraint: LOEUF 1.188 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.87

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.Pro49Arg 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
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-pro49 (accessed [today's date]).

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