Is HAND2 p.Pro8Leu (c.23C>T) pathogenic?

HAND2 p.Pro8Leu (c.23C>T) is classified Uncertain significance in HAND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-02). AlphaMissense: likely pathogenic (0.7975); No allele count reported in gnomAD v4.1 (AN 1,367,370); Associated with Inborn genetic diseases.

What condition is associated with HAND2 p.Pro8Leu (c.23C>T)?

HAND2 p.Pro8Leu (c.23C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HAND2 p.Pro8Leu (c.23C>T) in the general population?

HAND2 p.Pro8Leu (c.23C>T) is no allele count reported in gnomAD v4.1 (AN 1,367,370) (gnomAD).

What do computational predictors say about HAND2 p.Pro8Leu (c.23C>T)?

AlphaMissense predicts likely pathogenic (score 0.7975) — an in-silico prediction, not a clinical call.

HAND2 p.Pro8Leu

c.23C>T · rs2110907172 · VCV3104176

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7975 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,367,370)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7975	likely pathogenic
REVEL	0.409	indeterminate
SaProt	LLR -2.82	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP -2.1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 300 bp · p 0.15 · regional, not allelic
Overall
CADD	26.5	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

No allele count reported in gnomAD v4.1 (AN 1,367,370). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HAND2
Protein: p.Pro8Leu
Coding: c.23C>T
MANE Select: NM_021973
dbSNP: rs2110907172
Type: single nucleotide variant
Location: chr4:173529267 (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.Pro8= Benign/Likely benign ★★ same residue
HAND2 p.Pro8Ser Uncertain significance ★ ⚠ same residue
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.Ala23Val 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-pro8leu (accessed [today's date]).

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