Is CCKAR p.Arg336Trp (c.1006C>T) pathogenic?

CCKAR p.Arg336Trp (c.1006C>T) is classified Uncertain significance in CCKAR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-14). AlphaMissense: ambiguous (0.3829); Very rare (popmax 0.00999%, amr).

How common is CCKAR p.Arg336Trp (c.1006C>T) in the general population?

CCKAR p.Arg336Trp (c.1006C>T) is very rare (popmax 0.00999%, amr) (gnomAD).

What do computational predictors say about CCKAR p.Arg336Trp (c.1006C>T)?

AlphaMissense predicts ambiguous (score 0.3829) — an in-silico prediction, not a clinical call.

CCKAR p.Arg336Trp

c.1006C>T · VCV3828978

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00999%, amr)

Computational evidence

Protein change
AlphaMissense	0.3829	ambiguous
REVEL	0.622	indeterminate
SaProt	LLR -10.90	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.72, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 8,626 bp · p 0.69 · regional, not allelic
Overall
CADD	26.3	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 0.00999% Admixed American · 6/60,034 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.0013% 19/1,461,892 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00999%	10,006
Remaining individualsnot grpmax-eligible	0.0032%	31,256
European (non-Finnish)	0.000932%	107,277

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.Arg336Trp
Coding: c.1006C>T
MANE Select: NM_000730
Type: single nucleotide variant
Location: chr4:26481919 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 14 PDB
Residue 336: an α-helix

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-arg336trp (accessed [today's date]).

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