Is CIB4 p.Phe22Leu (c.66C>A) pathogenic?

CIB4 p.Phe22Leu (c.66C>A) is classified Uncertain significance in CIB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-16). AlphaMissense: likely pathogenic (0.995); Ultra-rare (popmax 0.033%, mid).

How common is CIB4 p.Phe22Leu (c.66C>A) in the general population?

CIB4 p.Phe22Leu (c.66C>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about CIB4 p.Phe22Leu (c.66C>A)?

AlphaMissense predicts likely pathogenic (score 0.995) — an in-silico prediction, not a clinical call.

CIB4 p.Phe22Leu

c.66C>A · rs141732203 · VCV2207414

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.995 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.995	likely pathogenic · top 1% in CIB4
REVEL	0.322	indeterminate
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.61, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 60 kb · p 0.65 · regional, not allelic
Overall
CADD	24.1	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 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.000744% 12/1,613,464 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
African / African-American	0.00933%	10,714
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	8.48e-05%	1,179,654

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.Phe22Leu
Coding: c.66C>A
MANE Select: NM_001029881
dbSNP: rs141732203
Type: single nucleotide variant
Location: chr2:26640556 (GRCh38)
Gene constraint: LOEUF 1.456 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.07

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-phe22leu (accessed [today's date]).

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