HECW2 p.Pro431=
c.1293G>A · rs1531111 · VCV1285335
Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Common
common (popmax 97.6%, eas) — too common for a highly-penetrant pathogenic allele
Conditions
1
neurodevelopmental disorder with hypotonia, seizures, and absent language
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 -20 | GERP -3.9 |
| Overall | ||
| CADD | 0.015 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
97.6%
East Asian · 43,822/44,882 alleles
Filtering AF
96.9%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 96.6%
Overall
80%
1,291,312/1,614,066 alleles · common
exomes 1,181,537/1,461,880 · genomes 109,775/152,186 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 97.6% | 1 |
| Admixed American | 84.8% | 1 |
| Amishnot grpmax-eligible | 83.7% | 1 |
| Finnishnot grpmax-eligible | 83.5% | 1 |
| European (non-Finnish) | 81.6% | 1 |
| Remaining individualsnot grpmax-eligible | 78.6% | 1 |
| Ashkenazi Jewishnot grpmax-eligible | 77.5% | 1 |
| South Asian | 76.8% | 1 |
| Middle Eastern | 68.9% | 1 |
| African / African-American | 45.1% | 2 |
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
- HECW2
- Protein
- p.Pro431=
- Coding
- c.1293G>A
- MANE Select
- NM_001348768
- dbSNP
- rs1531111
- Type
- single nucleotide variant
- Location
- chr2:196319597 (GRCh38)
- Gene constraint
- LOEUF 0.498 · pLI 0.86 (gnomAD)
- Structure
- AlphaFold pLDDT 62.07 · 2 PDB
- Residue 431
- the 'disordered' region
Similar variants
- HECW2 p.Arg1191Gln Pathogenic ★★ same condition
- HECW2 p.Arg1191Trp Likely pathogenic ★★ same condition
- HECW2 p.Arg1330Trp Pathogenic ★★ same condition
- HECW2 p.Arg1495Ser Pathogenic/Likely pathogenic ★★ same condition
- HECW2 p.Asn1199Lys Pathogenic/Likely pathogenic ★★ same condition
- HECW2 p.Asn1199Ser Likely pathogenic ★★ ⚠ same condition
- HECW2 p.Leu1448Ser Likely pathogenic ★★ same condition
- HECW2 p.Ser1504Tyr Likely pathogenic ★★ 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/hecw2-p-pro431 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown