Is HAND2 p.Pro8Ser (c.22C>T) pathogenic?

HAND2 p.Pro8Ser (c.22C>T) is classified Uncertain significance in HAND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-18). AlphaMissense: likely benign (0.2788); Ultra-rare (popmax 0.0138%, afr); Associated with HAND2-related disorder.

What condition is associated with HAND2 p.Pro8Ser (c.22C>T)?

HAND2 p.Pro8Ser (c.22C>T) is associated with HAND2-related disorder (ClinVar).

How common is HAND2 p.Pro8Ser (c.22C>T) in the general population?

HAND2 p.Pro8Ser (c.22C>T) is ultra-rare (popmax 0.0138%, afr) (gnomAD).

What do computational predictors say about HAND2 p.Pro8Ser (c.22C>T)?

AlphaMissense predicts likely benign (score 0.2788) — an in-silico prediction, not a clinical call.

HAND2 p.Pro8Ser

c.22C>T · rs905723042 · VCV2629263

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2788 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0138%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

HAND2-related disorder

Computational evidence

Protein change
AlphaMissense	0.2788	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -1.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP -1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 300 bp · p 0.15 · regional, not allelic
Overall
CADD	23.4	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 0.0138% African / African-American · 9/65,084 alleles

Filtering AF 0.00718% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00529%

Overall 0.000732% 10/1,366,932 alleles · ultra-rare exomes 3/1,215,806 · genomes 7/151,126 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0138%	7,232
Remaining individualsnot grpmax-eligible	0.00192%	52,038

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: HAND2
Protein: p.Pro8Ser
Coding: c.22C>T
MANE Select: NM_021973
dbSNP: rs905723042
Type: single nucleotide variant
Location: chr4:173529268 (GRCh38)
Gene constraint: LOEUF 0.601 · pLI 0.89 (gnomAD)
Structure: AlphaFold pLDDT 67.30

Full HAND2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

HAND2-related disorder

Similar variants

HAND2 p.Pro8= Benign/Likely benign ★★ same residue
HAND2 p.Pro8Leu Uncertain significance ★ ⚠ same residue
HAND2 p.Glu38Gln Uncertain significance ★★ same condition
HAND2 p.Val83Leu Uncertain significance ★ ⚠ same condition
HAND2 p.Glu108= Likely benign same condition
HAND2 p.Pro84= Likely benign same condition
HAND2 p.Pro95fs Uncertain significance same condition
HAND2 p.Gly162Ser Uncertain significance ★★ ⚠ same type

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/hand2-p-pro8ser (accessed [today's date]).

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