Is CLN5 p.Pro100Thr (c.298C>A) pathogenic?

CLN5 p.Pro100Thr (c.298C>A) is classified Uncertain significance in CLN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-29). AlphaMissense: likely pathogenic (0.9047); Very rare (popmax 8.47e-05%, nfe).

How common is CLN5 p.Pro100Thr (c.298C>A) in the general population?

CLN5 p.Pro100Thr (c.298C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CLN5 p.Pro100Thr (c.298C>A)?

AlphaMissense predicts likely pathogenic (score 0.9047) — an in-silico prediction, not a clinical call.

CLN5 p.Pro100Thr

c.298C>A · rs2154034644 · VCV1334850

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9047 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9047	likely pathogenic
REVEL	0.944	strongly pathogenic-leaning
SaProt	LLR -6.63	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 8,867 bp · p 0.55 · regional, not allelic
Overall
CADD	25.9	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,010 alleles

Overall 6.84e-05% 1/1,461,838 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: CLN5
Protein: p.Pro100Thr
Coding: c.298C>A
MANE Select: NM_006493
dbSNP: rs2154034644
Type: single nucleotide variant
Location: chr13:76995187 (GRCh38)
Gene constraint: LOEUF 1.197 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 1 PDB
Residue 100: a disulfide bond

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

Similar variants

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
CLN5 p.Cys77Tyr Likely pathogenic ★★ ⚠ same type
CLN5 p.Gln183Ter 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/cln5-p-pro100thr (accessed [today's date]).

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