Is CLN5 p.Phe139Ser (c.416T>C) pathogenic?

CLN5 p.Phe139Ser (c.416T>C) is classified Uncertain significance in CLN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-07). AlphaMissense: likely pathogenic (0.9788); Absent from gnomAD v4.1.

How common is CLN5 p.Phe139Ser (c.416T>C) in the general population?

CLN5 p.Phe139Ser (c.416T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLN5 p.Phe139Ser (c.416T>C)?

AlphaMissense predicts likely pathogenic (score 0.9788) — an in-silico prediction, not a clinical call.

CLN5 p.Phe139Ser

c.416T>C · rs2034259131 · VCV1307600

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9788 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9788	likely pathogenic · top 8% in CLN5
REVEL	0.929	moderately pathogenic-leaning
SaProt	LLR -4.41	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 8,867 bp · p 0.55 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

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: CLN5
Protein: p.Phe139Ser
Coding: c.416T>C
MANE Select: NM_006493
dbSNP: rs2034259131
Type: single nucleotide variant
Location: chr13:76995978 (GRCh38)
Gene constraint: LOEUF 1.197 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 1 PDB
Residue 139: a disulfide bond

Full CLN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLN5 p.Phe139= Likely benign ★★ same residue
CLN5 p.Phe139Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CLN5 c.174-2A>G Likely pathogenic ★★ same type
CLN5 p.Arg150Ter Pathogenic ★★ same type
CLN5 p.Arg63His Pathogenic/Likely pathogenic ★★ ⚠ same type
CLN5 p.Arg96Ter Pathogenic/Likely pathogenic ★★ same type
CLN5 p.Asn143Ser Pathogenic/Likely pathogenic ★★ ⚠ same type
CLN5 p.Cys144Tyr 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/cln5-p-phe139ser (accessed [today's date]).

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