Is CIMAP1C p.Ala66Asp (c.197C>A) pathogenic?

CIMAP1C p.Ala66Asp (c.197C>A) is classified Uncertain significance in CIMAP1C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: ambiguous (0.4099); Very rare (popmax 8.48e-05%, nfe).

How common is CIMAP1C p.Ala66Asp (c.197C>A) in the general population?

CIMAP1C p.Ala66Asp (c.197C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CIMAP1C p.Ala66Asp (c.197C>A)?

AlphaMissense predicts ambiguous (score 0.4099) — an in-silico prediction, not a clinical call.

CIMAP1C p.Ala66Asp

c.197C>A · VCV4653870

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4099	ambiguous · top 8% in CIMAP1C
REVEL	0.237	benign-leaning
SaProt	LLR -6.20	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.62 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.3	GERP 0.46, phastCons 0.75
Regional constraint	o/e 0.93	unconstrained · MANE · 3,337 bp · p 0.17 · regional, not allelic
Overall
CADD	18.55	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 8.48e-05% European (non-Finnish) · 1/1,179,816 alleles

Overall 6.2e-05% 1/1,613,892 alleles · very rare exomes 1/1,461,544 · genomes 0/152,348 · joint denominator

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.Ala66Asp
Coding: c.197C>A
MANE Select: NM_175881
Type: single nucleotide variant
Location: chr15:75725186 (GRCh38)
Structure: AlphaFold pLDDT 69.94

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

Similar variants

CIMAP1C p.Ala66Thr Uncertain significance ★ ⚠ same residue
CIMAP1C p.Ala14Glu Uncertain significance ★ ⚠ same type
CIMAP1C p.Ala226Pro 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-ala66asp (accessed [today's date]).

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