Is CKLF p.Phe113Ser (c.338T>C) pathogenic?

CKLF p.Phe113Ser (c.338T>C) is classified Uncertain significance in CKLF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-05). AlphaMissense: ambiguous (0.4195); Ultra-rare (popmax 0.0334%, mid).

How common is CKLF p.Phe113Ser (c.338T>C) in the general population?

CKLF p.Phe113Ser (c.338T>C) is ultra-rare (popmax 0.0334%, mid) (gnomAD).

What do computational predictors say about CKLF p.Phe113Ser (c.338T>C)?

AlphaMissense predicts ambiguous (score 0.4195) — an in-silico prediction, not a clinical call.

CKLF p.Phe113Ser

c.338T>C · rs1180115754 · VCV2276843

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4195 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4195	ambiguous
REVEL	0.26	benign-leaning
SaProt	LLR -8.12	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 0.32	GERP -1.8, phastCons 0.005
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	13.53	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 0.0334% Middle Eastern · 2/5,994 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.0018% 29/1,613,928 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0334%	2,997
Remaining individualsnot grpmax-eligible	0.0192%	5,206
African / African-American	0.0187%	5,351
European (non-Finnish)	8.47e-05%	1,179,998

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: CKLF
Protein: p.Phe113Ser
Coding: c.338T>C
MANE Select: NM_016951
dbSNP: rs1180115754
Type: single nucleotide variant
Location: chr16:66565890 (GRCh38)
Gene constraint: LOEUF 1.716 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.68
Residue 113: the marvel domain

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

Similar variants

CKLF p.Val145= Benign ★★ same type
CKLF-CMTM1 p.His10Tyr Uncertain significance ★ ⚠ same type
CKLF-CMTM1 p.Ile56Val Uncertain significance ★ ⚠ same type
CKLF-CMTM1 p.Phe13Leu Uncertain significance ★ ⚠ same type
CKLF p.Ala126Val Uncertain significance ★ ⚠ same type
CKLF p.Arg130Gly Uncertain significance ★ ⚠ same type
CKLF p.Asp124Glu Uncertain significance ★ ⚠ same type
CKLF p.Asp124Gly 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/cklf-p-phe113ser (accessed [today's date]).

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