Is CIB4 p.Ser151Leu (c.452C>T) pathogenic?

CIB4 p.Ser151Leu (c.452C>T) is classified Uncertain significance in CIB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-18). AlphaMissense: ambiguous (0.3438); Ultra-rare (popmax 0.0423%, eas).

How common is CIB4 p.Ser151Leu (c.452C>T) in the general population?

CIB4 p.Ser151Leu (c.452C>T) is ultra-rare (popmax 0.0423%, eas) (gnomAD).

What do computational predictors say about CIB4 p.Ser151Leu (c.452C>T)?

AlphaMissense predicts ambiguous (score 0.3438) — an in-silico prediction, not a clinical call.

CIB4 p.Ser151Leu

c.452C>T · rs370969445 · VCV2569724

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3438 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0423%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3438	ambiguous
REVEL	0.124	moderately benign-leaning
SaProt	LLR -8.20	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 9.9	GERP 0.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 60 kb · p 0.65 · regional, not allelic
Overall
CADD	25.2	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 0.0423% East Asian · 19/44,888 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.023%

Overall 0.00205% 33/1,612,240 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0423%	2,363
Remaining individualsnot grpmax-eligible	0.0032%	31,222
African / African-American	0.00267%	37,431
Admixed American	0.00167%	59,990
European (non-Finnish)	0.000764%	130,950

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: CIB4
Protein: p.Ser151Leu
Coding: c.452C>T
MANE Select: NM_001029881
dbSNP: rs370969445
Type: single nucleotide variant
Location: chr2:26582900 (GRCh38)
Gene constraint: LOEUF 1.456 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.07
Residue 151: the ef-hand 3 domain

Full CIB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CIB4 p.Arg107Cys Uncertain significance ★ ⚠ same type
CIB4 p.Arg128Gln Uncertain significance ★ ⚠ same type
CIB4 p.Arg128Leu Uncertain significance ★ ⚠ same type
CIB4 p.Arg179Gln Uncertain significance ★ ⚠ same type
CIB4 p.Arg25Gly Uncertain significance ★ ⚠ same type
CIB4 p.Arg62Gln Uncertain significance ★ ⚠ same type
CIB4 p.Arg69Cys Uncertain significance ★ ⚠ same type
CIB4 p.Asn155Asp 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/cib4-p-ser151leu (accessed [today's date]).

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