Is HAND1 p.Ter216= (c.647G>A) pathogenic?

HAND1 p.Ter216= (c.647G>A) is classified Likely benign in HAND1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). Very rare (popmax 0.00802%, afr); Associated with hypoplastic left heart syndrome.

What condition is associated with HAND1 p.Ter216= (c.647G>A)?

HAND1 p.Ter216= (c.647G>A) is associated with hypoplastic left heart syndrome (ClinVar).

How common is HAND1 p.Ter216= (c.647G>A) in the general population?

HAND1 p.Ter216= (c.647G>A) is very rare (popmax 0.00802%, afr) (gnomAD).

HAND1 p.Ter216=

c.647G>A · rs749591449 · VCV2063908

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

stop-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00802%, afr)

Conditions

hypoplastic left heart syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	stop-loss	predicted loss-of-function
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.2, phastCons 1
Overall
CADD	14.35	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00802% African / African-American · 6/74,854 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00155% 25/1,609,580 alleles · very rare exomes 23/1,457,346 · genomes 2/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00802%	12,476
Remaining individualsnot grpmax-eligible	0.00321%	31,140
European (non-Finnish)	0.00136%	73,546
South Asian	0.0011%	90,972

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: HAND1
Protein: p.Ter216=
Coding: c.647G>A
MANE Select: NM_004821
dbSNP: rs749591449
Type: single nucleotide variant
Location: chr5:154475807 (GRCh38)
Gene constraint: LOEUF 1.188 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.87

Full HAND1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypoplastic left heart syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HAND1 p.Ala68Pro Uncertain significance ★★ ⚠ same condition
HAND1 p.Arg91Gly Uncertain significance ★★ ⚠ same condition
HAND1 p.Gln43Arg Uncertain significance ★★ ⚠ same condition
HAND1 p.Glu103Gly Uncertain significance ★★ ⚠ same condition
HAND1 p.Gly203Ala Uncertain significance ★★ ⚠ same condition
HAND1 p.Leu3Val Uncertain significance ★★ ⚠ same condition
HAND1 p.Pro125Arg Uncertain significance ★★ ⚠ same condition
HAND1 p.Pro188Ala Uncertain significance ★★ ⚠ same condition

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/hand1-p-ter216 (accessed [today's date]).

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