Is HAND2 p.Ala23Val (c.68C>T) pathogenic?

HAND2 p.Ala23Val (c.68C>T) is classified Uncertain significance in HAND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-10). AlphaMissense: ambiguous (0.3595); Ultra-rare (popmax 0.0622%, mid); Associated with Inborn genetic diseases.

What condition is associated with HAND2 p.Ala23Val (c.68C>T)?

HAND2 p.Ala23Val (c.68C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HAND2 p.Ala23Val (c.68C>T) in the general population?

HAND2 p.Ala23Val (c.68C>T) is ultra-rare (popmax 0.0622%, mid) (gnomAD).

What do computational predictors say about HAND2 p.Ala23Val (c.68C>T)?

AlphaMissense predicts ambiguous (score 0.3595) — an in-silico prediction, not a clinical call.

HAND2 p.Ala23Val

c.68C>T · rs1429239453 · VCV3104177

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3595 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0622%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3595	ambiguous
REVEL	0.405	indeterminate
SaProt	LLR -9.84	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.24, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 300 bp · p 0.15 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0622% Middle Eastern · 3/4,820 alleles

Filtering AF 0.0169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00901%

Overall 0.000492% 7/1,423,080 alleles · ultra-rare exomes 7/1,271,450 · genomes 0/151,630 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0622%	1,607
Remaining individualsnot grpmax-eligible	0.00184%	54,248
South Asian	0.00159%	62,916
European (non-Finnish)	0.000183%	547,061

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.Ala23Val
Coding: c.68C>T
MANE Select: NM_021973
dbSNP: rs1429239453
Type: single nucleotide variant
Location: chr4:173529222 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HAND2 p.Gly162Ser Uncertain significance ★★ ⚠ same condition
HAND2 p.Gly74Ser Uncertain significance ★★ ⚠ same condition
HAND2 p.Lys216Asn Uncertain significance ★★ ⚠ same condition
HAND2 p.Ala21Gly Uncertain significance ★ ⚠ same condition
HAND2 p.Ala21Ser Uncertain significance ★ ⚠ same condition
HAND2 p.Ala69Asp Conflicting classifications of pathogenicity ★ same condition
HAND2 p.Ala72Thr Uncertain significance ★ ⚠ same condition
HAND2 p.Ala72Val 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/hand2-p-ala23val (accessed [today's date]).

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