Is CIC p.Pro2159His (c.6476C>A) pathogenic?

CIC p.Pro2159His (c.6476C>A) is classified Likely benign in CIC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.1088); Rare (popmax 0.14%, mid); Associated with Inborn genetic diseases.

What condition is associated with CIC p.Pro2159His (c.6476C>A)?

CIC p.Pro2159His (c.6476C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CIC p.Pro2159His (c.6476C>A) in the general population?

CIC p.Pro2159His (c.6476C>A) is rare (popmax 0.14%, mid) (gnomAD).

What do computational predictors say about CIC p.Pro2159His (c.6476C>A)?

AlphaMissense predicts likely benign (score 0.1088) — an in-silico prediction, not a clinical call.

CIC p.Pro2159His

c.6476C>A · rs747055103 · VCV2672772

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1088 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.14%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1088	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.39, phastCons 0.99
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1250H vs ClinVar P2159H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.14% Middle Eastern · 8/5,706 alleles

Filtering AF 0.0697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0509%

Overall 0.00364% 58/1,595,350 alleles · rare exomes 48/1,443,148 · genomes 10/152,202 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.14%	713
Remaining individualsnot grpmax-eligible	0.013%	7,717
Admixed American	0.00691%	14,468
European (non-Finnish)	0.0029%	34,485
African / African-American	0.00269%	37,221
South Asian	0.00226%	44,271

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.Pro2159His
Coding: c.6476C>A
MANE Select: NM_001386298
dbSNP: rs747055103
Type: single nucleotide variant
Location: chr19:42293235 (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-pro2159his (accessed [today's date]).

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