Is HCK p.Val440Ile (c.1318G>A) pathogenic?

HCK p.Val440Ile (c.1318G>A) is classified Uncertain significance in HCK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: likely benign (0.1172); Very rare (popmax 0.00892%, eas).

How common is HCK p.Val440Ile (c.1318G>A) in the general population?

HCK p.Val440Ile (c.1318G>A) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about HCK p.Val440Ile (c.1318G>A)?

AlphaMissense predicts likely benign (score 0.1172) — an in-silico prediction, not a clinical call.

HCK p.Val440Ile

c.1318G>A · VCV4033945

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1172 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1172	likely benign
REVEL	0.464	indeterminate
SaProt	LLR -8.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 15 kb · p 4.9e-07 · regional, not allelic
Overall
CADD	23.1	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 0.00892% East Asian · 4/44,868 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00173% 28/1,614,146 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,217
South Asian	0.00768%	13,013
African / African-American	0.004%	25,009
Admixed American	0.00333%	30,011
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000932%	107,274

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: HCK
Protein: p.Val440Ile
Coding: c.1318G>A
MANE Select: NM_002110
Type: single nucleotide variant
Location: chr20:32099075 (GRCh38)
Gene constraint: LOEUF 0.795 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.93 · 42 PDB
Residue 440: the protein kinase domain; an α-helix

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

Similar variants

HCK p.Arg123Trp Uncertain significance ★★ ⚠ same type
HCK p.Glu75Gln Uncertain significance ★★ ⚠ same type
HCK p.Leu139Val Uncertain significance ★★ ⚠ same type
HCK p.Ser5Pro Uncertain significance ★★ ⚠ same type
HCK p.Ala44Thr Benign/Likely benign ★★ same type
HCK p.Asn64= Benign ★★ same type
HCK p.Asp231= Benign/Likely benign ★★ same type
HCK p.Glu110= Likely benign ★★ 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/hck-p-val440ile (accessed [today's date]).

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