Is CIMIP2B p.Ser197Arg (c.591C>G) pathogenic?

CIMIP2B p.Ser197Arg (c.591C>G) is classified Uncertain significance in CIMIP2B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-27). AlphaMissense: likely pathogenic (0.911); Ultra-rare (popmax 0.0152%, sas).

How common is CIMIP2B p.Ser197Arg (c.591C>G) in the general population?

CIMIP2B p.Ser197Arg (c.591C>G) is ultra-rare (popmax 0.0152%, sas) (gnomAD).

What do computational predictors say about CIMIP2B p.Ser197Arg (c.591C>G)?

AlphaMissense predicts likely pathogenic (score 0.911) — an in-silico prediction, not a clinical call.

CIMIP2B p.Ser197Arg

c.591C>G · VCV3493039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.911 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0152%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.911	likely pathogenic · top 1% in CIMIP2B
REVEL	0.187	benign-leaning
SaProt	LLR -7.28	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.33	acceptor gain · deltas
Pangolin	Δ0.27	gain · loss 0.13 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.3	GERP 0.8, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,818 bp · p 0.2 · regional, not allelic
Overall
CADD	26.3	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 0.0152% South Asian · 13/85,426 alleles

Filtering AF 0.00897% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00712%

Overall 0.00159% 25/1,576,954 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0152%	6,571
Admixed American	0.00186%	53,722
European (non-Finnish)	0.000947%	105,613

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: CIMIP2B
Protein: p.Ser197Arg
Coding: c.591C>G
MANE Select: NM_001164310
Type: single nucleotide variant
Location: chr9:35562528 (GRCh38)
Structure: AlphaFold pLDDT 68.93 · 2 PDB

Full CIMIP2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RUSC2 p.Cys1328Tyr Uncertain significance ★★ ⚠ same type
CIMIP2B p.Ala114Val Uncertain significance ★ ⚠ same type
CIMIP2B p.Ala165Thr Uncertain significance ★ ⚠ same type
CIMIP2B p.Ala190Thr Uncertain significance ★ ⚠ same type
CIMIP2B p.Ala2Val Uncertain significance ★ ⚠ same type
CIMIP2B p.Arg100Trp Uncertain significance ★ ⚠ same type
CIMIP2B p.Arg176Trp Uncertain significance ★ ⚠ same type
CIMIP2B p.Arg46Gln 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/cimip2b-p-ser197arg (accessed [today's date]).

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