Is CIC p.Leu1071Phe (c.3213G>T) pathogenic?

CIC p.Leu1071Phe (c.3213G>T) is classified Benign/Likely benign in CIC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-01). AlphaMissense: likely benign (0.2553); Rare (popmax 0.851%, sas).

How common is CIC p.Leu1071Phe (c.3213G>T) in the general population?

CIC p.Leu1071Phe (c.3213G>T) is rare (popmax 0.851%, sas) (gnomAD).

What do computational predictors say about CIC p.Leu1071Phe (c.3213G>T)?

AlphaMissense predicts likely benign (score 0.2553) — an in-silico prediction, not a clinical call.

CIC p.Leu1071Phe

c.3213G>T · rs200317945 · VCV736418

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2553 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.851%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.2553	likely benign
REVEL	0.092	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 6.6	GERP -1.1, phastCons 1
Overall
CADD	23.0	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 L162F vs ClinVar L1071F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.851% South Asian · 775/91,080 alleles

Filtering AF 0.801% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.781%

Overall 0.0517% 834/1,614,080 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.851%	118
Remaining individualsnot grpmax-eligible	0.0784%	1,276
Middle Eastern	0.0165%	6,062
East Asian	0.0111%	8,974
African / African-American	0.00133%	75,020
European (non-Finnish)	0.000254%	393,345

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.Leu1071Phe
Coding: c.3213G>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs200317945
Type: single nucleotide variant
Location: chr19:42287353 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Similar variants

CIC p.Leu1071= 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-leu1071phe (accessed [today's date]).

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