Is HAND1 p.Pro49Arg (c.146C>G) pathogenic?

HAND1 p.Pro49Arg (c.146C>G) is classified Uncertain significance in HAND1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). AlphaMissense: likely benign (0.2914); Ultra-rare (popmax 0.0115%, nfe); Associated with hypoplastic left heart syndrome.

What condition is associated with HAND1 p.Pro49Arg (c.146C>G)?

HAND1 p.Pro49Arg (c.146C>G) is associated with hypoplastic left heart syndrome (ClinVar).

How common is HAND1 p.Pro49Arg (c.146C>G) in the general population?

HAND1 p.Pro49Arg (c.146C>G) is ultra-rare (popmax 0.0115%, nfe) (gnomAD).

What do computational predictors say about HAND1 p.Pro49Arg (c.146C>G)?

AlphaMissense predicts likely benign (score 0.2914) — an in-silico prediction, not a clinical call.

HAND1 p.Pro49Arg

c.146C>G · rs748866943 · VCV2169888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2914 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypoplastic left heart syndrome

Computational evidence

Protein change
AlphaMissense	0.2914	likely benign
REVEL	0.378	indeterminate
SaProt	LLR -8.36	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 9.7	GERP 0.86, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,199 bp · p 0.97 · regional, not allelic
Overall
CADD	24.9	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

Grpmax group 0.0115% European (non-Finnish) · 136/1,179,686 alleles

Filtering AF 0.00994% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00932%

Overall 0.00912% 146/1,601,578 alleles · ultra-rare exomes 136/1,449,388 · genomes 10/152,190 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0115%	8,674
Remaining individualsnot grpmax-eligible	0.0112%	8,908
African / African-American	0.00267%	37,457
East Asian	0.00223%	44,866

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.Pro49Arg
Coding: c.146C>G
MANE Select: NM_004821
dbSNP: rs748866943
Type: single nucleotide variant
Location: chr5:154477863 (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.Pro49= Likely benign ★ 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-pro49arg (accessed [today's date]).

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