Is CIB4 p.Phe164Ser (c.491T>C) pathogenic?

CIB4 p.Phe164Ser (c.491T>C) is classified Uncertain significance in CIB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-23). AlphaMissense: likely pathogenic (0.9942); Very rare (popmax 0.0022%, sas).

How common is CIB4 p.Phe164Ser (c.491T>C) in the general population?

CIB4 p.Phe164Ser (c.491T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CIB4 p.Phe164Ser (c.491T>C)?

AlphaMissense predicts likely pathogenic (score 0.9942) — an in-silico prediction, not a clinical call.

CIB4 p.Phe164Ser

c.491T>C · rs764263564 · VCV2233027

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9942	likely pathogenic · top 1% in CIB4
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -16.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 60 kb · p 0.65 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 · 2/91,042 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000248% 4/1,613,668 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,521
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)	8.48e-05%	1,179,728

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.Phe164Ser
Coding: c.491T>C
MANE Select: NM_001029881
dbSNP: rs764263564
Type: single nucleotide variant
Location: chr2:26582861 (GRCh38)
Gene constraint: LOEUF 1.456 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.07
Residue 164: 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-phe164ser (accessed [today's date]).

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