Is CLTC p.Pro1663Leu (c.4988C>T) pathogenic?

CLTC p.Pro1663Leu (c.4988C>T) is classified Uncertain significance in CLTC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-23). AlphaMissense: likely benign (0.2786); Very rare (popmax 0.0011%, sas).

How common is CLTC p.Pro1663Leu (c.4988C>T) in the general population?

CLTC p.Pro1663Leu (c.4988C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CLTC p.Pro1663Leu (c.4988C>T)?

AlphaMissense predicts likely benign (score 0.2786) — an in-silico prediction, not a clinical call.

CLTC p.Pro1663Leu

c.4988C>T · rs762072071 · VCV2998352

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2786	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -8.88	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 10 kb · p 3.7e-15 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,014 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,461,124 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,014
European (non-Finnish)	0.000339%	294,910

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.Pro1663Leu
Coding: c.4988C>T
MANE Select: NM_004859
dbSNP: rs762072071
Type: single nucleotide variant
Location: chr17:59693812 (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

Similar variants

CLTC p.Pro1663= 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-pro1663leu (accessed [today's date]).

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