Is CLCC1 p.Ser519Phe (c.1556C>T) pathogenic?

CLCC1 p.Ser519Phe (c.1556C>T) is classified Uncertain significance in CLCC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.1153); Absent from gnomAD v4.1.

How common is CLCC1 p.Ser519Phe (c.1556C>T) in the general population?

CLCC1 p.Ser519Phe (c.1556C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCC1 p.Ser519Phe (c.1556C>T)?

AlphaMissense predicts likely benign (score 0.1153) — an in-silico prediction, not a clinical call.

CLCC1 p.Ser519Phe

c.1556C>T · VCV4229456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1153 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1153	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -10.00	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 0.45	GERP -2.2
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	13.81	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

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: CLCC1
Protein: p.Ser519Phe
Coding: c.1556C>T
MANE Select: NM_001377458
Type: single nucleotide variant
Location: chr1:108934770 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.13
Residue 519: the 'disordered' region; a UniProt-annotated variant site (found in a patient with sporadic als)

Full CLCC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCC1 p.Ser519Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CLCC1 p.Ser519Tyr Uncertain significance ★ ⚠ same residue
CLCC1 p.Asp25Glu Pathogenic/Likely pathogenic ★★ ⚠ same type
CLCC1 p.Ala245Thr Uncertain significance ★★ ⚠ same type
CLCC1 p.Ala522Thr Uncertain significance ★★ ⚠ same type
CLCC1 p.Arg208His Uncertain significance ★★ ⚠ same type
CLCC1 p.Arg377Trp Uncertain significance ★★ ⚠ same type
CLCC1 p.Arg381Trp Uncertain significance ★★ ⚠ 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/clcc1-p-ser519phe (accessed [today's date]).

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