Is CIMIP4 p.Pro73Ser (c.217C>T) pathogenic?

CIMIP4 p.Pro73Ser (c.217C>T) is classified Uncertain significance in CIMIP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-14). AlphaMissense: likely benign (0.0895); Very rare (popmax 0.00188%, amr).

How common is CIMIP4 p.Pro73Ser (c.217C>T) in the general population?

CIMIP4 p.Pro73Ser (c.217C>T) is very rare (popmax 0.00188%, amr) (gnomAD).

What do computational predictors say about CIMIP4 p.Pro73Ser (c.217C>T)?

AlphaMissense predicts likely benign (score 0.0895) — an in-silico prediction, not a clinical call.

CIMIP4 p.Pro73Ser

c.217C>T · rs750206669 · VCV2496199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00188%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0895	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.43	GERP -3.2, phastCons 0.033
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.24 · regional, not allelic
Overall
CADD	13.01	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 0.00188% Admixed American · 1/53,246 alleles

Filtering AF 0.000366% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000265%

Overall 0.000829% 13/1,567,932 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00494%	20,236
Admixed Americangrpmax	0.00188%	53,246
European (non-Finnish)	0.000778%	128,452

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CIMIP4
Protein: p.Pro73Ser
Coding: c.217C>T
MANE Select: NM_001163857
dbSNP: rs750206669
Type: single nucleotide variant
Location: chr22:37002109 (GRCh38)
Structure: AlphaFold pLDDT 60.78
Residue 73: the 'disordered' region

Full CIMIP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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CIMIP4 p.Ala107Val Uncertain significance ★ ⚠ same type
CIMIP4 p.Ala256Val Uncertain significance ★ ⚠ same type
CIMIP4 p.Ala31Val Uncertain significance ★ ⚠ same type
CIMIP4 p.Ala96Val Uncertain significance ★ ⚠ same type
CIMIP4 p.Arg206Gln Uncertain significance ★ same type
CIMIP4 p.Arg206Trp Uncertain significance ★ ⚠ same type
CIMIP4 p.Arg250Trp 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/cimip4-p-pro73ser (accessed [today's date]).

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