Is HCK p.Pro49Ala (c.145C>G) pathogenic?

HCK p.Pro49Ala (c.145C>G) is classified Likely benign in HCK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-10). AlphaMissense: likely benign (0.0596); Rare (popmax 0.151%, afr).

How common is HCK p.Pro49Ala (c.145C>G) in the general population?

HCK p.Pro49Ala (c.145C>G) is rare (popmax 0.151%, afr) (gnomAD).

What do computational predictors say about HCK p.Pro49Ala (c.145C>G)?

AlphaMissense predicts likely benign (score 0.0596) — an in-silico prediction, not a clinical call.

HCK p.Pro49Ala

c.145C>G · VCV4280799

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0596 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.151%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0596	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -6.96	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 -0.69	GERP -2.5
Regional constraint	o/e 0.95	unconstrained · MANE · 32 kb · p 0.33 · regional, not allelic
Overall
CADD	0.144	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.151% African / African-American · 113/75,004 alleles

Filtering AF 0.128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.12%

Overall 0.00874% 141/1,614,066 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.151%	664
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0144%	6,946
Admixed American	0.005%	20,000
European (non-Finnish)	0.00119%	84,286
South Asian	0.0011%	91,076

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.Pro49Ala
Coding: c.145C>G
MANE Select: NM_002110
Type: single nucleotide variant
Location: chr20:32071744 (GRCh38)
Gene constraint: LOEUF 0.795 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.93 · 42 PDB

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-pro49ala (accessed [today's date]).

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