Is HAND2 p.Glu108= (c.324G>A) pathogenic?

HAND2 p.Glu108= (c.324G>A) is classified Likely benign in HAND2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-03-16). Ultra-rare (popmax 0.0133%, amr); Associated with HAND2-related disorder.

What condition is associated with HAND2 p.Glu108= (c.324G>A)?

HAND2 p.Glu108= (c.324G>A) is associated with HAND2-related disorder (ClinVar).

How common is HAND2 p.Glu108= (c.324G>A) in the general population?

HAND2 p.Glu108= (c.324G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

HAND2 p.Glu108=

c.324G>A · rs775523513 · VCV3036281

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Conditions

HAND2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Overall
CADD	15.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/59,974 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000496% 8/1,613,440 alleles · ultra-rare exomes 7/1,461,370 · genomes 1/152,070 · joint denominator

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.Glu108=
Coding: c.324G>A
MANE Select: NM_021973
dbSNP: rs775523513
Type: single nucleotide variant
Location: chr4:173528966 (GRCh38)
Gene constraint: LOEUF 0.601 · pLI 0.89 (gnomAD)
Structure: AlphaFold pLDDT 67.30
Residue 108: the bhlh domain; 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.Pro84= 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-glu108 (accessed [today's date]).

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