Is CLTC p.Arg523Gln (c.1568G>A) pathogenic?

CLTC p.Arg523Gln (c.1568G>A) is classified Uncertain significance in CLTC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-30). AlphaMissense: likely pathogenic (0.5804); Absent from gnomAD v4.1.

How common is CLTC p.Arg523Gln (c.1568G>A) in the general population?

CLTC p.Arg523Gln (c.1568G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLTC p.Arg523Gln (c.1568G>A)?

AlphaMissense predicts likely pathogenic (score 0.5804) — an in-silico prediction, not a clinical call.

CLTC p.Arg523Gln

c.1568G>A · rs893167974 · VCV2572757

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5804 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5804	likely pathogenic
REVEL	0.444	indeterminate
SaProt	LLR -5.75	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 23 kb · p 5.1e-71 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLTC
Protein: p.Arg523Gln
Coding: c.1568G>A
MANE Select: NM_004859
dbSNP: rs893167974
Type: single nucleotide variant
Location: chr17:59664833 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.62 · 10 PDB
Residue 523: the 'flexible linker' region

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

Similar variants

CLTC p.Arg523Pro Uncertain significance ★ ⚠ same residue
CLTC p.Arg523= Likely benign ★ same residue
CLTC p.Arg1165Ter Likely pathogenic ★★ same type
CLTC p.Arg1251Ter Pathogenic/Likely pathogenic ★★ same type
CLTC p.Arg1311Ter Likely pathogenic ★★ same type
CLTC p.Arg63Ter Pathogenic ★★ same type
CLTC p.Pro890Leu Pathogenic/Likely pathogenic ★★ same type
CLTC p.Tyr1574Ter Pathogenic/Likely 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/cltc-p-arg523gln (accessed [today's date]).

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