Is CIB1 p.Ala146Val (c.437C>T) pathogenic?

CIB1 p.Ala146Val (c.437C>T) is classified Uncertain significance in CIB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-18). AlphaMissense: likely benign (0.081); Very rare (popmax 0.0022%, sas).

How common is CIB1 p.Ala146Val (c.437C>T) in the general population?

CIB1 p.Ala146Val (c.437C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CIB1 p.Ala146Val (c.437C>T)?

AlphaMissense predicts likely benign (score 0.081) — an in-silico prediction, not a clinical call.

CIB1 p.Ala146Val

c.437C>T · rs560810851 · VCV998758

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.081 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.081	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -8.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.53 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.4	GERP -2.6, phastCons 0.048
Regional constraint	o/e 0.97	unconstrained · MANE · 3,398 bp · p 0.67 · regional, not allelic
Overall
CADD	16.52	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 0.0022% South Asian · 2/91,086 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00155% 25/1,614,182 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,543
European (non-Finnish)	0.00186%	53,637
African / African-American	0.00133%	75,062

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: CIB1
Protein: p.Ala146Val
Coding: c.437C>T
MANE Select: NM_006384
dbSNP: rs560810851
Type: single nucleotide variant
Location: chr15:90231123 (GRCh38)
Gene constraint: LOEUF 1.233 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.37 · 9 PDB
Residue 146: a UniProt-annotated variant site (in ev3; absence of cib1 protein in homozygous patient cells); an α-helix

Full CIB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CIB1 p.Ala146= Likely benign ★★ same residue
CIB1 p.Ala146Thr Likely benign ★ ⚠ same residue
CIB1 p.Ala184Pro Uncertain significance ★★ ⚠ same type
CIB1 p.Ala66Thr Uncertain significance ★★ ⚠ same type
CIB1 p.Arg113His Uncertain significance ★★ ⚠ same type
CIB1 p.Arg143Gln Uncertain significance ★★ ⚠ same type
CIB1 p.Arg143Trp Uncertain significance ★★ ⚠ same type
CIB1 p.Arg72Gln 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/cib1-p-ala146val (accessed [today's date]).

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