Is HAND2 p.His15Arg (c.44A>G) pathogenic?

HAND2 p.His15Arg (c.44A>G) is classified Uncertain significance in HAND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). AlphaMissense: ambiguous (0.4366); No allele count reported in gnomAD v4.1 (AN 1,400,888); Associated with Inborn genetic diseases.

What condition is associated with HAND2 p.His15Arg (c.44A>G)?

HAND2 p.His15Arg (c.44A>G) is associated with Inborn genetic diseases (ClinVar).

How common is HAND2 p.His15Arg (c.44A>G) in the general population?

HAND2 p.His15Arg (c.44A>G) is no allele count reported in gnomAD v4.1 (AN 1,400,888) (gnomAD).

What do computational predictors say about HAND2 p.His15Arg (c.44A>G)?

AlphaMissense predicts ambiguous (score 0.4366) — an in-silico prediction, not a clinical call.

HAND2 p.His15Arg

c.44A>G · VCV3283443

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4366 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,400,888)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4366	ambiguous
REVEL	0.498	indeterminate
SaProt	LLR -7.34	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 300 bp · p 0.15 · regional, not allelic
Overall
CADD	25.8	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 1,400,888). 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.His15Arg
Coding: c.44A>G
MANE Select: NM_021973
Type: single nucleotide variant
Location: chr4:173529246 (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.Ala23Val Uncertain significance ★ same condition
HAND2 p.Ala69Asp Conflicting classifications of pathogenicity ★ same condition
HAND2 p.Ala72Thr 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-his15arg (accessed [today's date]).

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