Is HAND2 p.Pro95fs (c.282del) pathogenic?

HAND2 p.Pro95fs (c.282del) is classified Uncertain significance in HAND2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-04). Very rare (popmax 0.00136%, afr); Associated with HAND2-related disorder.

What condition is associated with HAND2 p.Pro95fs (c.282del)?

HAND2 p.Pro95fs (c.282del) is associated with HAND2-related disorder (ClinVar).

How common is HAND2 p.Pro95fs (c.282del) in the general population?

HAND2 p.Pro95fs (c.282del) is very rare (popmax 0.00136%, afr) (gnomAD).

HAND2 p.Pro95fs

c.282del · VCV3353539

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Conditions

HAND2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 2
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Region caveats
Repeat context	tandem	(CCGGCGC)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% African / African-American · 1/73,366 alleles

Overall 0.000126% 2/1,591,320 alleles · very rare exomes 2/1,439,442 · genomes 0/151,878 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00163%	61,238
African / African-Americangrpmax	0.00136%	73,366

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro95fs
Coding: c.282del
MANE Select: NM_021973
Type: Deletion
Location: chr4:173529008 (GRCh38)
Gene constraint: LOEUF 0.601 · pLI 0.89 (gnomAD)
Structure: AlphaFold pLDDT 67.30
Residue 95: the 'disordered' region

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

Disease context

HAND2-related disorder

Similar variants

HAND2 p.Pro95Ala Uncertain significance ★ ⚠ same residue
HAND2 p.Pro95Leu Uncertain significance ★ ⚠ same residue
HAND2 p.Glu38Gln Uncertain significance ★★ same condition
HAND2 p.Pro8Ser 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.Ala24_Ala32del Conflicting classifications of pathogenicity ★ 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-pro95fs (accessed [today's date]).

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