Is CIC p.Val265Met (c.793G>A) pathogenic?

CIC p.Val265Met (c.793G>A) is classified Uncertain significance in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-28). Ultra-rare (popmax 0.0635%, sas); Associated with intellectual developmental disorder, autosomal dominant 45.

What condition is associated with CIC p.Val265Met (c.793G>A)?

CIC p.Val265Met (c.793G>A) is associated with intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Val265Met (c.793G>A) in the general population?

CIC p.Val265Met (c.793G>A) is ultra-rare (popmax 0.0635%, sas) (gnomAD).

CIC p.Val265Met

c.793G>A · rs1449982993 · VCV1804939

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0635%, sas)

Conditions

intellectual developmental disorder, autosomal dominant 45

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP -1.2, phastCons 1
Overall
CADD	13.13	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0635% South Asian · 5/7,868 alleles

Filtering AF 0.025% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0162%

Overall 0.00427% 17/398,550 alleles · ultra-rare exomes 10/246,294 · genomes 7/152,256 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0635%	1,574
European (non-Finnish)	0.00531%	18,833

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.Val265Met
Coding: c.793G>A
MANE Select: NM_001386298
dbSNP: rs1449982993
Type: single nucleotide variant
Location: chr19:42272576 (GRCh38)
Structure: AlphaFold pLDDT 75.09
Residue 265: a UniProt-annotated variant site (in d2l2ad; no protein detected by western blot in patient fibroblasts; severely reduced rates of citrate transport)

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

Disease context

intellectual developmental disorder, autosomal dominant 45 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SLC25A1 p.Gln265Leu Uncertain significance ★★ ⚠ same residue
CIC c.3179+1G>T Pathogenic ★★ same condition
CIC c.5903-2A>G Likely pathogenic ★★ same condition
CIC p.Asn1136Ser Likely pathogenic ★★ same condition
CIC p.Gln1134Ter Pathogenic ★★ same condition
CIC p.Gln1799Ter Likely pathogenic ★★ same condition
CIC p.Ala1761Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala2064Thr 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-val265met (accessed [today's date]).

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