Is CCKAR p.Ala142Glu (c.425C>A) pathogenic?

CCKAR p.Ala142Glu (c.425C>A) is classified Uncertain significance in CCKAR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: likely pathogenic (0.9897); Very rare (popmax 0.00017%, nfe).

How common is CCKAR p.Ala142Glu (c.425C>A) in the general population?

CCKAR p.Ala142Glu (c.425C>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CCKAR p.Ala142Glu (c.425C>A)?

AlphaMissense predicts likely pathogenic (score 0.9897) — an in-silico prediction, not a clinical call.

CCKAR p.Ala142Glu

c.425C>A · VCV4649909

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9897 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9897	likely pathogenic · top 5% in CCKAR
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -14.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 8,626 bp · p 0.69 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00017% European (non-Finnish) · 2/1,179,726 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,496 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,584
European (non-Finnish)grpmax	0.00017%	589,863

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CCKAR
Protein: p.Ala142Glu
Coding: c.425C>A
MANE Select: NM_000730
Type: single nucleotide variant
Location: chr4:26485838 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 14 PDB
Residue 142: a disulfide bond; an α-helix

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

Similar variants

CCKAR p.Ala142Val Uncertain significance ★ ⚠ same residue
CCKAR p.Ala193Thr Uncertain significance ★ ⚠ same type
CCKAR p.Ala332Thr Uncertain significance ★ ⚠ same type
CCKAR p.Ala341Thr Uncertain significance ★ ⚠ same type
CCKAR p.Arg150Pro Uncertain significance ★ ⚠ same type
CCKAR p.Arg197Cys Uncertain significance ★ ⚠ same type
CCKAR p.Arg297Gln Uncertain significance ★ ⚠ same type
CCKAR p.Arg313Cys 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/cckar-p-ala142glu (accessed [today's date]).

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