Is CCKAR p.Trp39Arg (c.115T>A) pathogenic?

CCKAR p.Trp39Arg (c.115T>A) is classified Uncertain significance in CCKAR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). AlphaMissense: ambiguous (0.4231); Very rare (popmax 0.00667%, amr).

How common is CCKAR p.Trp39Arg (c.115T>A) in the general population?

CCKAR p.Trp39Arg (c.115T>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about CCKAR p.Trp39Arg (c.115T>A)?

AlphaMissense predicts ambiguous (score 0.4231) — an in-silico prediction, not a clinical call.

CCKAR p.Trp39Arg

c.115T>A · VCV4221899

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4231 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4231	ambiguous
REVEL	0.108	moderately benign-leaning
SaProt	LLR -6.65	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 8,626 bp · p 0.69 · regional, not allelic
Overall
CADD	22.6	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 0.00667% Admixed American · 4/59,966 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000434% 7/1,613,276 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,991
European (non-Finnish)	0.000254%	393,147

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.Trp39Arg
Coding: c.115T>A
MANE Select: NM_000730
Type: single nucleotide variant
Location: chr4:26489482 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 14 PDB

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

Similar variants

CCKAR p.Ala142Glu Uncertain significance ★ ⚠ same type
CCKAR p.Ala142Val Uncertain significance ★ ⚠ same type
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

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-trp39arg (accessed [today's date]).

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