Is CILK1 p.Ser255Arg (c.765T>G) pathogenic?

CILK1 p.Ser255Arg (c.765T>G) is classified Uncertain significance in CILK1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-26). AlphaMissense: likely benign (0.2713); Ultra-rare (popmax 0.02%, amr).

How common is CILK1 p.Ser255Arg (c.765T>G) in the general population?

CILK1 p.Ser255Arg (c.765T>G) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about CILK1 p.Ser255Arg (c.765T>G)?

AlphaMissense predicts likely benign (score 0.2713) — an in-silico prediction, not a clinical call.

CILK1 p.Ser255Arg

c.765T>G · rs754158707 · VCV1204616

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2713 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2713	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -8.58	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 -8.2	GERP -5.6
Regional constraint	o/e 0.86	unconstrained · MANE · 36 kb · p 7.8e-05 · regional, not allelic
Overall
CADD	1.388	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 0.02% Admixed American · 12/60,008 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.000743% 12/1,614,044 alleles · ultra-rare

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: CILK1
Protein: p.Ser255Arg
Coding: c.765T>G
MANE Select: NM_014920
dbSNP: rs754158707
Type: single nucleotide variant
Location: chr6:53016149 (GRCh38)
Gene constraint: LOEUF 0.774 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.47
Residue 255: the protein kinase domain

Full CILK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CILK1 c.1344-4T>A Uncertain significance ★★ same type
CILK1 p.Ala629Thr Uncertain significance ★★ ⚠ same type
CILK1 p.Arg124Gln Uncertain significance ★★ ⚠ same type
CILK1 p.Arg151Gln Uncertain significance ★★ ⚠ same type
CILK1 p.Arg262Lys Uncertain significance ★★ ⚠ same type
CILK1 p.Arg280Gln Uncertain significance ★★ ⚠ same type
CILK1 p.Arg332Gln Uncertain significance ★★ ⚠ same type
CILK1 p.Arg475Trp 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/cilk1-p-ser255arg (accessed [today's date]).

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