Is HAND1 p.Pro189Ser (c.565C>T) pathogenic?

HAND1 p.Pro189Ser (c.565C>T) is classified Uncertain significance in HAND1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-09). AlphaMissense: likely benign (0.0693); Ultra-rare (popmax 0.0494%, mid); Associated with hypoplastic left heart syndrome.

What condition is associated with HAND1 p.Pro189Ser (c.565C>T)?

HAND1 p.Pro189Ser (c.565C>T) is associated with hypoplastic left heart syndrome (ClinVar).

How common is HAND1 p.Pro189Ser (c.565C>T) in the general population?

HAND1 p.Pro189Ser (c.565C>T) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

What do computational predictors say about HAND1 p.Pro189Ser (c.565C>T)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

HAND1 p.Pro189Ser

c.565C>T · rs1389554299 · VCV1958995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypoplastic left heart syndrome

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.212	benign-leaning
SaProt	LLR -6.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP -0.053, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,199 bp · p 0.97 · regional, not allelic
Overall
CADD	16.22	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 0.0494% Middle Eastern · 3/6,076 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00062% 10/1,613,726 alleles · ultra-rare exomes 9/1,461,508 · genomes 1/152,218 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,025
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	0.000509%	196,618

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.Pro189Ser
Coding: c.565C>T
MANE Select: NM_004821
dbSNP: rs1389554299
Type: single nucleotide variant
Location: chr5:154475889 (GRCh38)
Gene constraint: LOEUF 1.188 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.87
Residue 189: 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.Pro189Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro189ser (accessed [today's date]).

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