Is CIMAP1C p.Ala226Pro (c.676G>C) pathogenic?

CIMAP1C p.Ala226Pro (c.676G>C) is classified Uncertain significance in CIMAP1C (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-02). AlphaMissense: likely benign (0.0954); Very rare (popmax 0.00167%, amr).

How common is CIMAP1C p.Ala226Pro (c.676G>C) in the general population?

CIMAP1C p.Ala226Pro (c.676G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CIMAP1C p.Ala226Pro (c.676G>C)?

AlphaMissense predicts likely benign (score 0.0954) — an in-silico prediction, not a clinical call.

CIMAP1C p.Ala226Pro

c.676G>C · rs147726214 · VCV2493178

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0954	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -4.74	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 -1.2	GERP -1.9
Regional constraint	o/e 0.93	unconstrained · MANE · 3,337 bp · p 0.17 · regional, not allelic
Overall
CADD	2.043	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 0.00167% Admixed American · 1/59,996 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000682% 11/1,613,844 alleles · very rare exomes 9/1,461,698 · genomes 2/152,146 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,996
European (non-Finnish)	0.000847%	118,004

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: CIMAP1C
Protein: p.Ala226Pro
Coding: c.676G>C
MANE Select: NM_175881
dbSNP: rs147726214
Type: single nucleotide variant
Location: chr15:75727391 (GRCh38)
Structure: AlphaFold pLDDT 69.94

Full CIMAP1C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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CIMAP1C p.Ala66Asp Uncertain significance ★ ⚠ same type
CIMAP1C p.Ala66Thr Uncertain significance ★ ⚠ same type
CIMAP1C p.Arg110His Uncertain significance ★ ⚠ same type
CIMAP1C p.Arg136His Uncertain significance ★ ⚠ same type
CIMAP1C p.Arg146Trp Uncertain significance ★ ⚠ same type
CIMAP1C p.Arg147His Uncertain significance ★ ⚠ same type
CIMAP1C p.Arg215Cys 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/cimap1c-p-ala226pro (accessed [today's date]).

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