Is CHKA p.Pro66Ser (c.196C>T) pathogenic?

CHKA p.Pro66Ser (c.196C>T) is classified Likely benign in CHKA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.087); Rare (popmax 0.329%, sas).

How common is CHKA p.Pro66Ser (c.196C>T) in the general population?

CHKA p.Pro66Ser (c.196C>T) is rare (popmax 0.329%, sas) (gnomAD).

What do computational predictors say about CHKA p.Pro66Ser (c.196C>T)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

CHKA p.Pro66Ser

c.196C>T · VCV4228139

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.329%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -10.47	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -0.45, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 67 kb · p 0.94 · regional, not allelic
Overall
CADD	17.45	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 0.329% South Asian · 77/23,404 alleles

Filtering AF 0.27% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.248%

Overall 0.00965% 108/1,118,922 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.329%	304
Middle Eastern	0.0528%	1,895
Remaining individualsnot grpmax-eligible	0.0291%	3,440
European (non-Finnish)	0.00186%	53,861
African / African-American	0.00166%	60,258

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: CHKA
Protein: p.Pro66Ser
Coding: c.196C>T
MANE Select: NM_001277
Type: single nucleotide variant
Location: chr11:68120982 (GRCh38)
Gene constraint: LOEUF 0.926 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.95 · 26 PDB
Residue 66: the 'disordered' region

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

Similar variants

CHKA p.Glu230Lys Uncertain significance ★★ ⚠ same type
CHKA p.Arg141Trp Likely pathogenic ★ same type
CHKA p.Gly344Ter Likely pathogenic ★ same type
CHKA p.Phe341Leu Likely pathogenic ★ same type
CHKA p.Pro194Ser Likely pathogenic ★ same type
CHKA p.Ala188Thr Uncertain significance ★ ⚠ same type
CHKA p.Ala27Thr Uncertain significance ★ ⚠ same type
CHKA p.Ala385Thr Uncertain significance ★ ⚠ 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/chka-p-pro66ser (accessed [today's date]).

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