Is CKLF p.Val96Met (c.286G>A) pathogenic?

CKLF p.Val96Met (c.286G>A) is classified Uncertain significance in CKLF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-08). AlphaMissense: likely benign (0.2109); Ultra-rare (popmax 0.0167%, amr).

How common is CKLF p.Val96Met (c.286G>A) in the general population?

CKLF p.Val96Met (c.286G>A) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about CKLF p.Val96Met (c.286G>A)?

AlphaMissense predicts likely benign (score 0.2109) — an in-silico prediction, not a clinical call.

CKLF p.Val96Met

c.286G>A · rs936974405 · VCV2235448

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2109 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2109	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -9.07	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 0.78	GERP -0.67, phastCons 0.96
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	22.5	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 0.0167% Admixed American · 10/59,986 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000743% 12/1,614,010 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,999
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Val96Met
Coding: c.286G>A
MANE Select: NM_016951
dbSNP: rs936974405
Type: single nucleotide variant
Location: chr16:66563170 (GRCh38)
Gene constraint: LOEUF 1.716 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.68
Residue 96: 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-val96met (accessed [today's date]).

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