Is CLN8 p.Pro89Ser (c.265C>T) pathogenic?

CLN8 p.Pro89Ser (c.265C>T) is classified Uncertain significance in CLN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-06-09). AlphaMissense: likely benign (0.1299); Very rare (popmax 0.00167%, amr).

How common is CLN8 p.Pro89Ser (c.265C>T) in the general population?

CLN8 p.Pro89Ser (c.265C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CLN8 p.Pro89Ser (c.265C>T)?

AlphaMissense predicts likely benign (score 0.1299) — an in-silico prediction, not a clinical call.

CLN8 p.Pro89Ser

c.265C>T · rs1486320972 · VCV432562

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1299 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1299	likely benign
REVEL	0.334	indeterminate
SaProt	LLR -8.09	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.72	GERP -0.058, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	14.85	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

Grpmax group 0.00167% Admixed American · 1/60,022 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,894 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,022
European (non-Finnish)	0.000169%	590,016

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: CLN8
Protein: p.Pro89Ser
Coding: c.265C>T
MANE Select: NM_018941
dbSNP: rs1486320972
Type: single nucleotide variant
Location: chr8:1771319 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.47 · 3 PDB
Residue 89: the tlc domain

Full CLN8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLN8 p.Pro89Arg Uncertain significance ★★ ⚠ same residue
CLN8 p.Pro89Ala Uncertain significance ★ ⚠ same residue
CLN8 p.Pro89Thr Uncertain significance ★ ⚠ same residue
CLN8 p.Arg204Cys Pathogenic/Likely pathogenic ★★ same type
CLN8 p.Arg204His Likely pathogenic ★★ same type
CLN8 p.Arg24Gly Pathogenic ★★ same type
CLN8 p.Arg70Cys Pathogenic/Likely pathogenic ★★ same type
CLN8 p.Arg70His 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/cln8-p-pro89ser (accessed [today's date]).

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