Is CILK1 p.Ser356Phe (c.1067C>T) pathogenic?

CILK1 p.Ser356Phe (c.1067C>T) is classified Uncertain significance in CILK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-20). AlphaMissense: likely benign (0.0923); Very rare (popmax 0.00263%, nfe).

How common is CILK1 p.Ser356Phe (c.1067C>T) in the general population?

CILK1 p.Ser356Phe (c.1067C>T) is very rare (popmax 0.00263%, nfe) (gnomAD).

What do computational predictors say about CILK1 p.Ser356Phe (c.1067C>T)?

AlphaMissense predicts likely benign (score 0.0923) — an in-silico prediction, not a clinical call.

CILK1 p.Ser356Phe

c.1067C>T · rs1764726098 · VCV2526770

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0923	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -8.47	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 8.5	GERP 0.82, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 36 kb · p 7.8e-05 · regional, not allelic
Overall
CADD	22.1	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 0.00263% European (non-Finnish) · 31/1,180,036 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00212% 31/1,461,886 alleles · very 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.Ser356Phe
Coding: c.1067C>T
MANE Select: NM_014920
dbSNP: rs1764726098
Type: single nucleotide variant
Location: chr6:53013747 (GRCh38)
Gene constraint: LOEUF 0.774 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.47

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-ser356phe (accessed [today's date]).

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