Is CLTC p.Phe1258Ser (c.3773T>C) pathogenic?

CLTC p.Phe1258Ser (c.3773T>C) is classified Uncertain significance in CLTC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-23). AlphaMissense: likely pathogenic (0.9572); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with CLTC p.Phe1258Ser (c.3773T>C)?

CLTC p.Phe1258Ser (c.3773T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CLTC p.Phe1258Ser (c.3773T>C) in the general population?

CLTC p.Phe1258Ser (c.3773T>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about CLTC p.Phe1258Ser (c.3773T>C)?

AlphaMissense predicts likely pathogenic (score 0.9572) — an in-silico prediction, not a clinical call.

CLTC p.Phe1258Ser

c.3773T>C · rs1332973535 · VCV2894569

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9572 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9572	likely pathogenic
REVEL	0.377	indeterminate
SaProt	LLR -13.49	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.32	constrained · MANE · 1,389 bp · p 1.1e-33 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.004% African / African-American · 3/74,940 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,614,026 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.Phe1258Ser
Coding: c.3773T>C
MANE Select: NM_004859
dbSNP: rs1332973535
Type: single nucleotide variant
Location: chr17:59682914 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.62 · 10 PDB
Residue 1258: 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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLTC p.Phe1258Leu Uncertain significance ★ ⚠ same residue
CLTC p.Ala1259Thr Uncertain significance ★★ ⚠ same condition
CLTC p.Ala198Thr Uncertain significance ★★ ⚠ same condition
CLTC p.Arg923His Uncertain significance ★★ ⚠ same condition
CLTC p.Arg949His Uncertain significance ★★ ⚠ same condition
CLTC p.Asn1078Ser Uncertain significance ★★ ⚠ same condition
CLTC p.Asn1145Ser Uncertain significance ★★ ⚠ same condition
CLTC p.Asn340Ser 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-phe1258ser (accessed [today's date]).

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