Is CMIP p.Ala730Ser (c.2188G>T) pathogenic?

CMIP p.Ala730Ser (c.2188G>T) is classified Uncertain significance in CMIP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely benign (0.0768); Ultra-rare (popmax 0.0165%, mid).

How common is CMIP p.Ala730Ser (c.2188G>T) in the general population?

CMIP p.Ala730Ser (c.2188G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CMIP p.Ala730Ser (c.2188G>T)?

AlphaMissense predicts likely benign (score 0.0768) — an in-silico prediction, not a clinical call.

CMIP p.Ala730Ser

c.2188G>T · VCV4230437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0768 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0768	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -5.38	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 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 18 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	23.3	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 0.0165% Middle Eastern · 1/6,072 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000834%

Overall 0.00125% 20/1,599,274 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,072
European (non-Finnish)	0.00162%	61,809

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: CMIP
Protein: p.Ala730Ser
Coding: c.2188G>T
MANE Select: NM_198390
Type: single nucleotide variant
Location: chr16:81705595 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.52

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

Similar variants

CMIP c.1638+10G>A Likely benign ★★ same type
CMIP c.2269-10C>T Benign/Likely benign ★★ same type
CMIP p.Asn295= Benign ★★ same type
CMIP p.Leu369= Likely benign ★★ same type
CMIP p.Pro414= Benign ★★ same type
CMIP p.Val547= Benign ★★ same type
CMIP c.1035-1G>A Uncertain significance ★ same type
CMIP p.Ala113Thr 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/cmip-p-ala730ser (accessed [today's date]).

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