Is CCKAR p.Ser260Cys (c.778A>T) pathogenic?

CCKAR p.Ser260Cys (c.778A>T) is classified Uncertain significance in CCKAR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.0672); Rare (popmax 0.148%, mid).

How common is CCKAR p.Ser260Cys (c.778A>T) in the general population?

CCKAR p.Ser260Cys (c.778A>T) is rare (popmax 0.148%, mid) (gnomAD).

What do computational predictors say about CCKAR p.Ser260Cys (c.778A>T)?

AlphaMissense predicts likely benign (score 0.0672) — an in-silico prediction, not a clinical call.

CCKAR p.Ser260Cys

c.778A>T · VCV4649900

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0672 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0672	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -9.33	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 -4.5	GERP -3.9
Regional constraint	o/e 1.02	unconstrained · MANE · 8,626 bp · p 0.69 · regional, not allelic
Overall
CADD	13.09	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.148% Middle Eastern · 9/6,068 alleles

Filtering AF 0.0773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.00335% 54/1,610,684 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.148%	674
Admixed American	0.0284%	3,524
Remaining individualsnot grpmax-eligible	0.00802%	12,472
African / African-American	0.00802%	12,473
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,466
European (non-Finnish)	0.00136%	73,593

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.Ser260Cys
Coding: c.778A>T
MANE Select: NM_000730
Type: single nucleotide variant
Location: chr4:26482147 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 14 PDB
Residue 260: the 'disordered' region

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-ser260cys (accessed [today's date]).

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