Is CLTC p.Ser1127Phe (c.3380C>T) pathogenic?

CLTC p.Ser1127Phe (c.3380C>T) is classified Uncertain significance in CLTC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-05). AlphaMissense: likely pathogenic (0.9975); Absent from gnomAD v4.1.

How common is CLTC p.Ser1127Phe (c.3380C>T) in the general population?

CLTC p.Ser1127Phe (c.3380C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLTC p.Ser1127Phe (c.3380C>T)?

AlphaMissense predicts likely pathogenic (score 0.9975) — an in-silico prediction, not a clinical call.

CLTC p.Ser1127Phe

c.3380C>T · rs2143592469 · VCV1309162

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9975 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9975	likely pathogenic
REVEL	0.697	pathogenic-leaning
SaProt	LLR -10.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 620 bp · p 0.002 · regional, not allelic
Overall
CADD	29.1	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

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.Ser1127Phe
Coding: c.3380C>T
MANE Select: NM_004859
dbSNP: rs2143592469
Type: single nucleotide variant
Location: chr17:59681777 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.62 · 10 PDB
Residue 1127: the 'heavy chain arm' region; the 'proximal segment' region

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

Similar variants

CLTC p.Ser1127Thr 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
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-ser1127phe (accessed [today's date]).

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