Is HCK p.Ser5Pro (c.13T>C) pathogenic?

HCK p.Ser5Pro (c.13T>C) is classified Uncertain significance in HCK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-09). AlphaMissense: likely benign (0.0692); Ultra-rare (popmax 0.0689%, mid).

How common is HCK p.Ser5Pro (c.13T>C) in the general population?

HCK p.Ser5Pro (c.13T>C) is ultra-rare (popmax 0.0689%, mid) (gnomAD).

What do computational predictors say about HCK p.Ser5Pro (c.13T>C)?

AlphaMissense predicts likely benign (score 0.0692) — an in-silico prediction, not a clinical call.

HCK p.Ser5Pro

c.13T>C · rs957448914 · VCV2460095

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0692 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0689%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0692	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -6.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.11	GERP -1.8, phastCons 0.018
Regional constraint	o/e 0.95	unconstrained · MANE · 32 kb · p 0.33 · regional, not allelic
Overall
CADD	21.4	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 0.0689% Middle Eastern · 3/4,352 alleles

Filtering AF 0.0196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00211% 27/1,280,934 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0689%	1,451
Admixed American	0.0377%	2,654
Remaining individualsnot grpmax-eligible	0.00636%	15,726
Finnishnot grpmax-eligible	0.00206%	48,514
African / African-American	0.00155%	64,506
European (non-Finnish)	0.000995%	100,485

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.Ser5Pro
Coding: c.13T>C
MANE Select: NM_002110
dbSNP: rs957448914
Type: single nucleotide variant
Location: chr20:32052437 (GRCh38)
Gene constraint: LOEUF 0.795 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.93 · 42 PDB
Residue 5: the 'disordered' region

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

Similar variants

HCK p.Ser5Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
HCK p.Arg123Trp Uncertain significance ★★ ⚠ same type
HCK p.Glu75Gln Uncertain significance ★★ ⚠ same type
HCK p.Leu139Val 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-ser5pro (accessed [today's date]).

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