Is CLTC p.Pro1450Ser (c.4348C>T) pathogenic?

CLTC p.Pro1450Ser (c.4348C>T) is classified Uncertain significance in CLTC (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-22). AlphaMissense: likely benign (0.2443); Very rare (popmax 0.00167%, amr).

How common is CLTC p.Pro1450Ser (c.4348C>T) in the general population?

CLTC p.Pro1450Ser (c.4348C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CLTC p.Pro1450Ser (c.4348C>T)?

AlphaMissense predicts likely benign (score 0.2443) — an in-silico prediction, not a clinical call.

CLTC p.Pro1450Ser

c.4348C>T · VCV4778034

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2443 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2443	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -8.54	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 1.7, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 10 kb · p 3.7e-15 · regional, not allelic
Overall
CADD	26.4	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 0.00167% Admixed American · 1/60,022 alleles

Overall 0.000137% 2/1,461,500 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,022
European (non-Finnish)	8.48e-05%	1,179,748

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.Pro1450Ser
Coding: c.4348C>T
MANE Select: NM_004859
Type: single nucleotide variant
Location: chr17:59683899 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.62 · 10 PDB
Residue 1450: the 'heavy chain arm' region; the 'proximal segment' region; the 'involved in binding clathrin light chain' 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.Pro1450Leu Uncertain significance ★★ ⚠ same residue
CLTC p.Pro1450Ala Uncertain significance ★ ⚠ 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-pro1450ser (accessed [today's date]).

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