Is CLN3 p.Met409Val (c.1225A>G) pathogenic?

CLN3 p.Met409Val (c.1225A>G) is classified Conflicting classifications of pathogenicity in CLN3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2023-02-21). AlphaMissense: likely benign (0.3342); Ultra-rare (popmax 0.011%, sas); Associated with CLN3-related disorders.

What condition is associated with CLN3 p.Met409Val (c.1225A>G)?

CLN3 p.Met409Val (c.1225A>G) is associated with CLN3-related disorders, neuronal ceroid lipofuscinosis 3, neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN3 p.Met409Val (c.1225A>G) in the general population?

CLN3 p.Met409Val (c.1225A>G) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about CLN3 p.Met409Val (c.1225A>G)?

AlphaMissense predicts likely benign (score 0.3342) — an in-silico prediction, not a clinical call.

CLN3 p.Met409Val

c.1225A>G · rs776443981 · VCV205101

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3342 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CLN3-related disorders

Computational evidence

Protein change
AlphaMissense	0.3342	likely benign
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -9.23	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.071, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 14 kb · p 0.08 · regional, not allelic
Overall
CADD	24.0	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 0.011% South Asian · 10/91,076 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00198% 32/1,613,748 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
Admixed American	0.005%	19,994
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00267%	37,421
East Asian	0.00223%	44,888
Finnishnot grpmax-eligible	0.00157%	63,880
European (non-Finnish)	0.00102%	98,333

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.Met409Val
Coding: c.1225A>G
MANE Select: NM_001042432
dbSNP: rs776443981
Type: single nucleotide variant
Location: chr16:28477608 (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

CLN3-related disorders

Also linked: neuronal ceroid lipofuscinosis 3 neuronal ceroid lipofuscinosis

Similar variants

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
CLN3 c.222+1G>A Likely pathogenic ★★ same condition
CLN3 c.46+1G>A Likely 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-met409val (accessed [today's date]).

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