Is HAND2 p.Pro84= (c.252G>A) pathogenic?

HAND2 p.Pro84= (c.252G>A) is classified Likely benign in HAND2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-13). Ultra-rare (popmax 0.0733%, sas); Associated with HAND2-related disorder.

What condition is associated with HAND2 p.Pro84= (c.252G>A)?

HAND2 p.Pro84= (c.252G>A) is associated with HAND2-related disorder (ClinVar).

How common is HAND2 p.Pro84= (c.252G>A) in the general population?

HAND2 p.Pro84= (c.252G>A) is ultra-rare (popmax 0.0733%, sas) (gnomAD).

HAND2 p.Pro84=

c.252G>A · rs562712418 · VCV3049302

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0733%, sas)

Conditions

HAND2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.65	GERP -0.43, phastCons 0.99
Overall
CADD	14.26	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0733% South Asian · 54/73,676 alleles

Filtering AF 0.0576% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.052%

Overall 0.0038% 57/1,498,310 alleles · ultra-rare exomes 53/1,346,458 · genomes 4/151,852 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0733%	1,364
Remaining individualsnot grpmax-eligible	0.00523%	19,123

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.Pro84=
Coding: c.252G>A
MANE Select: NM_021973
dbSNP: rs562712418
Type: single nucleotide variant
Location: chr4:173529038 (GRCh38)
Gene constraint: LOEUF 0.601 · pLI 0.89 (gnomAD)
Structure: AlphaFold pLDDT 67.30
Residue 84: 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.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.Pro95fs Uncertain significance same condition
HAND2 p.Gly162Ser Uncertain significance ★★ ⚠ same type
HAND2 p.Gly74Ser Uncertain significance ★★ ⚠ same type
HAND2 p.Lys216Asn 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-pro84 (accessed [today's date]).

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