Is CIB3 p.Arg71His (c.212G>A) pathogenic?

CIB3 p.Arg71His (c.212G>A) is classified Uncertain significance in CIB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-10). AlphaMissense: likely benign (0.1995); Ultra-rare (popmax 0.01%, amr).

How common is CIB3 p.Arg71His (c.212G>A) in the general population?

CIB3 p.Arg71His (c.212G>A) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about CIB3 p.Arg71His (c.212G>A)?

AlphaMissense predicts likely benign (score 0.1995) — an in-silico prediction, not a clinical call.

CIB3 p.Arg71His

c.212G>A · rs186929589 · VCV2591395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1995 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1995	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -11.84	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -3.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 12 kb · p 0.5 · regional, not allelic
Overall
CADD	25.0	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 0.01% Admixed American · 6/59,986 alleles

Filtering AF 0.00571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00595% 96/1,613,822 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,998
Remaining individualsnot grpmax-eligible	0.008%	12,500
European (non-Finnish)	0.00695%	14,389
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,580
African / African-American	0.00266%	37,529

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: CIB3
Protein: p.Arg71His
Coding: c.212G>A
MANE Select: NM_054113
dbSNP: rs186929589
Type: single nucleotide variant
Location: chr19:16168271 (GRCh38)
Gene constraint: LOEUF 1.277 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.17 · 3 PDB
Residue 71: the ef-hand 1 domain; an α-helix

Full CIB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CIB3 p.Arg71Cys Uncertain significance ★ ⚠ same residue
CIB3 p.Ala102Pro Uncertain significance ★ ⚠ same type
CIB3 p.Ala125Val Uncertain significance ★ ⚠ same type
CIB3 p.Ala142Val Uncertain significance ★ ⚠ same type
CIB3 p.Ala38Thr Uncertain significance ★ ⚠ same type
CIB3 p.Arg104Cys Uncertain significance ★ ⚠ same type
CIB3 p.Arg137Gln Uncertain significance ★ ⚠ same type
CIB3 p.Arg137Trp 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/cib3-p-arg71his (accessed [today's date]).

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