Is CLN5 p.Phe312Ser (c.935T>C) pathogenic?

CLN5 p.Phe312Ser (c.935T>C) is classified Uncertain significance in CLN5 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2023-09-19). AlphaMissense: ambiguous (0.5203); Rare (popmax 0.125%, eas); Associated with neuronal ceroid lipofuscinosis 5.

What condition is associated with CLN5 p.Phe312Ser (c.935T>C)?

CLN5 p.Phe312Ser (c.935T>C) is associated with neuronal ceroid lipofuscinosis 5, neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN5 p.Phe312Ser (c.935T>C) in the general population?

CLN5 p.Phe312Ser (c.935T>C) is rare (popmax 0.125%, eas) (gnomAD).

What do computational predictors say about CLN5 p.Phe312Ser (c.935T>C)?

AlphaMissense predicts ambiguous (score 0.5203) — an in-silico prediction, not a clinical call.

CLN5 p.Phe312Ser

c.935T>C · rs201767993 · VCV580580

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5203 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.125%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

neuronal ceroid lipofuscinosis 5

Computational evidence

Protein change
AlphaMissense	0.5203	ambiguous
REVEL	0.663	pathogenic-leaning
SaProt	LLR -9.63	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 8,867 bp · p 0.55 · regional, not allelic
Overall
CADD	24.3	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 0.125% East Asian · 56/44,844 alleles

Filtering AF 0.0987% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0893%

Overall 0.0041% 66/1,609,538 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.125%	801
Middle Eastern	0.0166%	6,038
South Asian	0.00889%	11,247
Remaining individualsnot grpmax-eligible	0.00161%	62,254

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.Phe312Ser
Coding: c.935T>C
MANE Select: NM_006493
dbSNP: rs201767993
Type: single nucleotide variant
Location: chr13:77000827 (GRCh38)
Gene constraint: LOEUF 1.197 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 1 PDB
Residue 312: the 'membrane-anchoring' region

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

Disease context

neuronal ceroid lipofuscinosis 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuronal ceroid lipofuscinosis

For CLN5 disease (Orphanet):

Onset: Infancy

Similar variants

CLN5 p.Phe312Leu Uncertain significance ★ ⚠ same residue
CLN5 p.Phe312fs Pathogenic/Likely pathogenic ★★ same residue
CLN5 c.174-2A>G Likely pathogenic ★★ same condition
CLN5 p.Arg150Ter Pathogenic ★★ same condition
CLN5 p.Arg63His Pathogenic/Likely pathogenic ★★ ⚠ same condition
CLN5 p.Arg96Ter Pathogenic/Likely pathogenic ★★ same condition
CLN5 p.Asn143Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
CLN5 p.Cys144Tyr 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/cln5-p-phe312ser (accessed [today's date]).

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