Is HECW2 p.Ser665= (c.1995C>T) pathogenic?

HECW2 p.Ser665= (c.1995C>T) is classified Likely benign in HECW2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-01). Very rare (popmax 0.00216%, nfe).

How common is HECW2 p.Ser665= (c.1995C>T) in the general population?

HECW2 p.Ser665= (c.1995C>T) is very rare (popmax 0.00216%, nfe) (gnomAD).

HECW2 p.Ser665=

c.1995C>T · VCV4822233

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00216%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.7	GERP -4.4
Overall
CADD	0.531	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00216% European (non-Finnish) · 25/1,155,912 alleles

Filtering AF 0.00148% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00126%

Overall 0.00198% 31/1,566,774 alleles · very rare exomes 29/1,414,570 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00497%	20,113
Finnishnot grpmax-eligible	0.00321%	31,123
European (non-Finnish)grpmax	0.00216%	46,237
African / African-American	0.00136%	73,686

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser665=
Coding: c.1995C>T
MANE Select: NM_001348768
Type: single nucleotide variant
Location: chr2:196318895 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 62.07 · 2 PDB
Residue 665: the 'disordered' region

Full HECW2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HECW2 p.Arg1191Gln Pathogenic ★★ same type
HECW2 p.Arg1191Trp Likely pathogenic ★★ same type
HECW2 p.Arg1330Trp Pathogenic ★★ same type
HECW2 p.Arg1495Ser Pathogenic/Likely pathogenic ★★ same type
HECW2 p.Asn1199Lys Pathogenic/Likely pathogenic ★★ same type
HECW2 p.Asn1199Ser Likely pathogenic ★★ ⚠ same type
HECW2 p.Leu1448Ser Likely pathogenic ★★ same type
HECW2 p.Ser1504Tyr Likely pathogenic ★★ 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/hecw2-p-ser665 (accessed [today's date]).

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