Is CLTC p.Pro1663= (c.4989G>A) pathogenic?

CLTC p.Pro1663= (c.4989G>A) is classified Likely benign in CLTC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-24). Ultra-rare (popmax 0.033%, sas); Associated with intellectual disability, autosomal dominant 56.

What condition is associated with CLTC p.Pro1663= (c.4989G>A)?

CLTC p.Pro1663= (c.4989G>A) is associated with intellectual disability, autosomal dominant 56 (ClinVar).

How common is CLTC p.Pro1663= (c.4989G>A) in the general population?

CLTC p.Pro1663= (c.4989G>A) is ultra-rare (popmax 0.033%, sas) (gnomAD).

CLTC p.Pro1663=

c.4989G>A · rs144269102 · VCV1535158

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, sas)

Conditions

intellectual disability, autosomal dominant 56

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -3.6
Overall
CADD	3.879	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% South Asian · 30/91,014 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.0031% 50/1,613,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.033%	3,034
Admixed American	0.00334%	29,948
African / African-American	0.00267%	37,403
Remaining individualsnot grpmax-eligible	0.0016%	62,434
European (non-Finnish)	0.00127%	78,639

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.Pro1663=
Coding: c.4989G>A
MANE Select: NM_004859
dbSNP: rs144269102
Type: single nucleotide variant
Location: chr17:59693813 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.62 · 10 PDB
Residue 1663: the 'heavy chain arm' region; the 'proximal segment' region; the 'trimerization' region; a UniProt-annotated variant site (in mrd56)

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.Pro1663Leu 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-pro1663 (accessed [today's date]).

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