Is CLN3 p.Ser335Pro (c.1003T>C) pathogenic?

CLN3 p.Ser335Pro (c.1003T>C) is classified Uncertain significance in CLN3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-12). AlphaMissense: likely pathogenic (0.9742); Very rare (popmax 0.00133%, afr); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN3 p.Ser335Pro (c.1003T>C)?

CLN3 p.Ser335Pro (c.1003T>C) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN3 p.Ser335Pro (c.1003T>C) in the general population?

CLN3 p.Ser335Pro (c.1003T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CLN3 p.Ser335Pro (c.1003T>C)?

AlphaMissense predicts likely pathogenic (score 0.9742) — an in-silico prediction, not a clinical call.

CLN3 p.Ser335Pro

c.1003T>C · rs1567257016 · VCV574919

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.9742	likely pathogenic · top 7% in CLN3
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -16.04	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 9.1	GERP 1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 14 kb · p 0.08 · regional, not allelic
Overall
CADD	27.3	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

Grpmax group 0.00133% African / African-American · 1/74,966 alleles

Overall 0.000137% 2/1,461,610 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,966
European (non-Finnish)	8.48e-05%	1,179,894

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: CLN3
Protein: p.Ser335Pro
Coding: c.1003T>C
MANE Select: NM_001042432
dbSNP: rs1567257016
Type: single nucleotide variant
Location: chr16:28482158 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.81

Full CLN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuronal ceroid lipofuscinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLN3 p.Ser335= Likely benign ★ same residue
CLN3 p.Ser335Tyr Likely pathogenic ★ same residue
CLN3 c.1056+1G>A Likely pathogenic ★★ same condition
CLN3 c.1056+1G>T Likely pathogenic ★★ same condition
CLN3 c.1056+3A>C Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.1197+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.1198-1G>T Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.125+1G>C Pathogenic ★★ same condition

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/cln3-p-ser335pro (accessed [today's date]).

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