Is CIC p.Ala1683Val (c.5048C>T) pathogenic?

CIC p.Ala1683Val (c.5048C>T) is classified Likely benign in CIC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-16). AlphaMissense: likely benign (0.0843); Ultra-rare (popmax 0.0132%, sas).

How common is CIC p.Ala1683Val (c.5048C>T) in the general population?

CIC p.Ala1683Val (c.5048C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about CIC p.Ala1683Val (c.5048C>T)?

AlphaMissense predicts likely benign (score 0.0843) — an in-silico prediction, not a clinical call.

CIC p.Ala1683Val

c.5048C>T · rs574832764 · VCV1176080

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0843 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0843	likely benign
REVEL	0.161	moderately 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 4.1	GERP 0.22, phastCons 1
Overall
CADD	19.18	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 A774V vs ClinVar A1683V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% South Asian · 12/91,070 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00638% 103/1,613,618 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,589
Remaining individualsnot grpmax-eligible	0.008%	12,498
European (non-Finnish)	0.00704%	14,215
East Asian	0.00446%	22,438
Finnishnot grpmax-eligible	0.00157%	63,782

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.Ala1683Val
Coding: c.5048C>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs574832764
Type: single nucleotide variant
Location: chr19:42291089 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Similar variants

CIC p.Ala1683= Likely benign ★★ same residue
CIC c.3179+1G>A Likely pathogenic ★★ same type
CIC c.3179+1G>T Pathogenic ★★ same type
CIC c.5903-2A>G Likely pathogenic ★★ same type
CIC p.Asn1136Ser Likely pathogenic ★★ same type
CIC p.Gln1134Ter Pathogenic ★★ same type
CIC p.Gln1799Ter Likely pathogenic ★★ same type
SLC25A1 c.821+1G>A Pathogenic ★★ 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/cic-p-ala1683val (accessed [today's date]).

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