Is CLYBL p.Pro288Leu (c.863C>T) pathogenic?

CLYBL p.Pro288Leu (c.863C>T) is classified Uncertain significance in CLYBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely benign (0.0815); Very rare (popmax 0.00439%, sas).

How common is CLYBL p.Pro288Leu (c.863C>T) in the general population?

CLYBL p.Pro288Leu (c.863C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about CLYBL p.Pro288Leu (c.863C>T)?

AlphaMissense predicts likely benign (score 0.0815) — an in-silico prediction, not a clinical call.

CLYBL p.Pro288Leu

c.863C>T · VCV4230409

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0815 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0815	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -8.92	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 0.94	GERP 1.6, phastCons 0.16
Regional constraint	o/e 1.05	unconstrained · MANE · 285 kb · p 0.27 · regional, not allelic
Overall
CADD	17.75	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 0.00439% South Asian · 4/91,028 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000744% 12/1,613,592 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,757
African / African-American	0.00401%	24,937
Remaining individualsnot grpmax-eligible	0.0032%	31,237
Admixed American	0.00167%	59,962
European (non-Finnish)	0.00017%	589,925

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: CLYBL
Protein: p.Pro288Leu
Coding: c.863C>T
MANE Select: NM_206808
Type: single nucleotide variant
Location: chr13:99870998 (GRCh38)
Gene constraint: LOEUF 1.186 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.00 · 3 PDB
Residue 288: a UniProt-annotated variant site (loss of the protein product; reduction of circulating vitamin b12); an α-helix

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

Similar variants

CLYBL p.Ala116Val Uncertain significance ★ ⚠ same type
CLYBL p.Ala13Asp Uncertain significance ★ ⚠ same type
CLYBL p.Ala13Val Uncertain significance ★ ⚠ same type
CLYBL p.Ala16Val Uncertain significance ★ ⚠ same type
CLYBL p.Ala17Ser Uncertain significance ★ ⚠ same type
CLYBL p.Ala17Thr Uncertain significance ★ ⚠ same type
CLYBL p.Ala17Val Uncertain significance ★ ⚠ same type
CLYBL p.Ala213Ser 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/clybl-p-pro288leu (accessed [today's date]).

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