Is CLTC p.Ala864Thr (c.2590G>A) pathogenic?

CLTC p.Ala864Thr (c.2590G>A) is classified Conflicting classifications of pathogenicity in CLTC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-20). AlphaMissense: likely benign (0.0857); Absent from gnomAD v4.1; Associated with intellectual disability, autosomal dominant 56.

What condition is associated with CLTC p.Ala864Thr (c.2590G>A)?

CLTC p.Ala864Thr (c.2590G>A) is associated with intellectual disability, autosomal dominant 56 (ClinVar).

How common is CLTC p.Ala864Thr (c.2590G>A) in the general population?

CLTC p.Ala864Thr (c.2590G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLTC p.Ala864Thr (c.2590G>A)?

AlphaMissense predicts likely benign (score 0.0857) — an in-silico prediction, not a clinical call.

CLTC p.Ala864Thr

c.2590G>A · rs2509144215 · VCV1805692

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0857 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 56

Computational evidence

Protein change
AlphaMissense	0.0857	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -6.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.69, phastCons 1
Regional constraint	o/e 0.36	constrained · MANE · 13 kb · p 3.4e-42 · regional, not allelic
Overall
CADD	23.5	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.Ala864Thr
Coding: c.2590G>A
MANE Select: NM_004859
dbSNP: rs2509144215
Type: single nucleotide variant
Location: chr17:59676982 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.62 · 10 PDB
Residue 864: the 'heavy chain arm' region; the 'proximal segment' region

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

Disease context

intellectual disability, autosomal dominant 56 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLTC p.Ala864Val Uncertain significance ★ ⚠ same residue
CLTC p.Arg1165Ter Likely pathogenic ★★ same condition
CLTC p.Arg1251Ter Pathogenic/Likely pathogenic ★★ same condition
CLTC p.Arg1311Ter Likely pathogenic ★★ same condition
CLTC p.Arg63Ter Pathogenic ★★ same condition
CLTC p.Pro890Leu Pathogenic/Likely pathogenic ★★ same condition
CLTC p.Tyr1574Ter Pathogenic/Likely pathogenic ★★ same condition
CLTC c.4605+3T>A 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/cltc-p-ala864thr (accessed [today's date]).

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