Is CIC p.Met1209Val (c.3625A>G) pathogenic?

CIC p.Met1209Val (c.3625A>G) is classified Likely benign in CIC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.2348); Ultra-rare (popmax 0.0448%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CIC p.Met1209Val (c.3625A>G)?

CIC p.Met1209Val (c.3625A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CIC p.Met1209Val (c.3625A>G) in the general population?

CIC p.Met1209Val (c.3625A>G) is ultra-rare (popmax 0.0448%, nfe) (gnomAD).

What do computational predictors say about CIC p.Met1209Val (c.3625A>G)?

AlphaMissense predicts likely benign (score 0.2348) — an in-silico prediction, not a clinical call.

CIC p.Met1209Val

c.3625A>G · rs201633759 · VCV2364955

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2348 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0448%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2348	likely benign
REVEL	0.213	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM M300V vs ClinVar M1209V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0448% European (non-Finnish) · 527/1,175,836 alleles

Filtering AF 0.0416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0403%

Overall 0.0343% 550/1,603,926 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0448%	2,231
Remaining individualsnot grpmax-eligible	0.0177%	5,652
Finnishnot grpmax-eligible	0.0128%	7,843
African / African-American	0.004%	24,987
East Asian	0.00225%	44,512

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: CIC
Protein: p.Met1209Val
Coding: c.3625A>G
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs201633759
Type: single nucleotide variant
Location: chr19:42287942 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIC c.2795-2056C>T Uncertain significance ★★ ⚠ same condition
CIC p.Ala1228Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala1445Gly Uncertain significance ★★ ⚠ same condition
CIC p.Ala1750Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala1975Gly Uncertain significance ★★ ⚠ same condition
CIC p.Ala2463Thr Uncertain significance ★★ ⚠ same condition
CIC p.Arg1205Trp Uncertain significance ★★ ⚠ same condition
CIC p.Arg1481Gln Uncertain significance ★★ ⚠ same condition

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/cic-p-met1209val (accessed [today's date]).

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