Is HAND2 p.Gln217Pro (c.650A>C) pathogenic?

HAND2 p.Gln217Pro (c.650A>C) is classified Likely benign in HAND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.8513); Rare (popmax 0.193%, afr).

How common is HAND2 p.Gln217Pro (c.650A>C) in the general population?

HAND2 p.Gln217Pro (c.650A>C) is rare (popmax 0.193%, afr) (gnomAD).

What do computational predictors say about HAND2 p.Gln217Pro (c.650A>C)?

AlphaMissense predicts likely pathogenic (score 0.8513) — an in-silico prediction, not a clinical call.

HAND2 p.Gln217Pro

c.650A>C · rs140861359 · VCV2703085

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8513 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.193%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8513	likely pathogenic
REVEL	0.556	indeterminate
SaProt	LLR -6.40	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 54 bp · p 0.013 · regional, not allelic
Overall
CADD	25.9	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

Grpmax group 0.193% African / African-American · 145/74,994 alleles

Filtering AF 0.168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.158%

Overall 0.00962% 155/1,610,526 alleles · rare exomes 64/1,458,262 · genomes 91/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.193%	517
Remaining individualsnot grpmax-eligible	0.0144%	6,937
Admixed American	0.00167%	60,012

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.Gln217Pro
Coding: c.650A>C
MANE Select: NM_021973
dbSNP: rs140861359
Type: single nucleotide variant
Location: chr4:173527281 (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

Similar variants

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
HAND2 p.Ala21Thr Likely benign ★★ same type
HAND2 p.Ala25= 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-gln217pro (accessed [today's date]).

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