Is HAND2 p.Ser195Arg (c.585C>A) pathogenic?

HAND2 p.Ser195Arg (c.585C>A) is classified Uncertain significance in HAND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-10). AlphaMissense: likely pathogenic (0.9202); Very rare (popmax 0.00882%, nfe).

How common is HAND2 p.Ser195Arg (c.585C>A) in the general population?

HAND2 p.Ser195Arg (c.585C>A) is very rare (popmax 0.00882%, nfe) (gnomAD).

What do computational predictors say about HAND2 p.Ser195Arg (c.585C>A)?

AlphaMissense predicts likely pathogenic (score 0.9202) — an in-silico prediction, not a clinical call.

HAND2 p.Ser195Arg

c.585C>A · rs368269900 · VCV1981696

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9202 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00882%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9202	likely pathogenic
REVEL	0.577	indeterminate
SaProt	LLR -7.88	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.98, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,489 bp · p 0.97 · regional, not allelic
Overall
CADD	23.1	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 0.00882% European (non-Finnish) · 104/1,179,658 alleles

Filtering AF 0.00741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00692%

Overall 0.00657% 106/1,613,466 alleles · very rare exomes 103/1,461,342 · genomes 3/152,124 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00882%	11,343
Remaining individualsnot grpmax-eligible	0.0032%	31,238

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.Ser195Arg
Coding: c.585C>A
MANE Select: NM_021973
dbSNP: rs368269900
Type: single nucleotide variant
Location: chr4:173527346 (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-ser195arg (accessed [today's date]).

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