Is HECW2 p.Arg900Gln (c.2699G>A) pathogenic?

HECW2 p.Arg900Gln (c.2699G>A) is classified Uncertain significance in HECW2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: likely benign (0.1113); Ultra-rare (popmax 0.0134%, eas); Associated with Inborn genetic diseases.

What condition is associated with HECW2 p.Arg900Gln (c.2699G>A)?

HECW2 p.Arg900Gln (c.2699G>A) is associated with Inborn genetic diseases (ClinVar).

How common is HECW2 p.Arg900Gln (c.2699G>A) in the general population?

HECW2 p.Arg900Gln (c.2699G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about HECW2 p.Arg900Gln (c.2699G>A)?

AlphaMissense predicts likely benign (score 0.1113) — an in-silico prediction, not a clinical call.

HECW2 p.Arg900Gln

c.2699G>A · VCV3857362

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1113 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1113	likely benign
REVEL	0.495	indeterminate
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 14 kb · p 0.49 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,690 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00395%

Overall 0.000931% 15/1,611,180 alleles · ultra-rare exomes 15/1,459,014 · genomes 0/152,166 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,448
European (non-Finnish)	0.000764%	130,966

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.Arg900Gln
Coding: c.2699G>A
MANE Select: NM_001348768
Type: single nucleotide variant
Location: chr2:196306603 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 62.07 · 2 PDB
Residue 900: the 'interaction with tp73' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HECW2 p.Arg900Trp Uncertain significance ★★ ⚠ same residue
HECW2 p.Arg900Pro Uncertain significance ★ same residue
HECW2 p.Arg900= Benign ★★ same residue
HECW2 p.Arg1191Gln Pathogenic ★★ same condition
HECW2 p.Ser1505Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
HECW2 p.Ala1028Val Uncertain significance ★★ ⚠ same condition
HECW2 p.Ala1317Thr Uncertain significance ★★ ⚠ same condition
HECW2 p.Ala523Val 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/hecw2-p-arg900gln (accessed [today's date]).

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