Is HAND2 p.Pro95Ala (c.283C>G) pathogenic?

HAND2 p.Pro95Ala (c.283C>G) is classified Uncertain significance in HAND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). AlphaMissense: likely benign (0.0585); Very rare (popmax 0.00572%, sas).

How common is HAND2 p.Pro95Ala (c.283C>G) in the general population?

HAND2 p.Pro95Ala (c.283C>G) is very rare (popmax 0.00572%, sas) (gnomAD).

What do computational predictors say about HAND2 p.Pro95Ala (c.283C>G)?

AlphaMissense predicts likely benign (score 0.0585) — an in-silico prediction, not a clinical call.

HAND2 p.Pro95Ala

c.283C>G · rs75152023 · VCV1975490

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0585 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00572%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0585	likely benign
REVEL	0.367	indeterminate
SaProt	LLR -6.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 300 bp · p 0.15 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00572% South Asian · 5/87,390 alleles

Filtering AF 0.00217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00141%

Overall 0.00195% 31/1,591,230 alleles · very rare exomes 28/1,439,458 · genomes 3/151,772 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00794%	12,598
South Asiangrpmax	0.00572%	17,478
Remaining individualsnot grpmax-eligible	0.0049%	20,406
European (non-Finnish)	0.00154%	65,107

Finnish 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.Pro95Ala
Coding: c.283C>G
MANE Select: NM_021973
dbSNP: rs75152023
Type: single nucleotide variant
Location: chr4:173529007 (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

Similar variants

HAND2 p.Pro95Leu Uncertain significance ★ ⚠ same residue
HAND2 p.Pro95fs Uncertain significance same residue
HAND2 p.Glu38Gln Uncertain significance ★★ same type
HAND2 p.Gly162Ser Uncertain significance ★★ ⚠ same type
HAND2 p.Gly74Ser Uncertain significance ★★ ⚠ same type
HAND2 p.Lys216Asn Uncertain significance ★★ ⚠ same type
HAND2 c.556-18C>G Benign/Likely benign ★★ same type
HAND2 p.Ala164= Likely benign ★★ 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-pro95ala (accessed [today's date]).

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