Is CLTC p.Ala592Val (c.1775C>T) pathogenic?

CLTC p.Ala592Val (c.1775C>T) is classified Uncertain significance in CLTC (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-01). AlphaMissense: likely pathogenic (0.9107); Very rare (popmax 8.48e-05%, nfe).

How common is CLTC p.Ala592Val (c.1775C>T) in the general population?

CLTC p.Ala592Val (c.1775C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CLTC p.Ala592Val (c.1775C>T)?

AlphaMissense predicts likely pathogenic (score 0.9107) — an in-silico prediction, not a clinical call.

CLTC p.Ala592Val

c.1775C>T · rs757885268 · VCV932428

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9107 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9107	likely pathogenic
REVEL	0.319	indeterminate
SaProt	LLR -9.33	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 23 kb · p 5.1e-71 · regional, not allelic
Overall
CADD	27.0	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,710 alleles

Overall 6.84e-05% 1/1,461,418 alleles · very rare

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: CLTC
Protein: p.Ala592Val
Coding: c.1775C>T
MANE Select: NM_004859
dbSNP: rs757885268
Type: single nucleotide variant
Location: chr17:59666233 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.62 · 10 PDB
Residue 592: the 'heavy chain arm' region; the 'distal segment' region

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

Similar variants

CLTC p.Ala592= 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
CLTC p.Tyr803Ter 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-ala592val (accessed [today's date]).

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