Is CLN3 p.His74= (c.222T>C) pathogenic?

CLN3 p.His74= (c.222T>C) is classified Conflicting classifications of pathogenicity in CLN3 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2024-05-06). Ultra-rare (popmax 0.0108%, nfe); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN3 p.His74= (c.222T>C)?

CLN3 p.His74= (c.222T>C) is associated with neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis 3 (ClinVar).

How common is CLN3 p.His74= (c.222T>C) in the general population?

CLN3 p.His74= (c.222T>C) is ultra-rare (popmax 0.0108%, nfe) (gnomAD).

CLN3 p.His74=

c.222T>C · rs201225986 · VCV457951

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, nfe)

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.31	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3	GERP -0.55
Overall
CADD	0.583	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0108% European (non-Finnish) · 127/1,175,048 alleles

Filtering AF 0.00923% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00867%

Overall 0.0101% 162/1,607,466 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0344%	2,904
Remaining individualsnot grpmax-eligible	0.0161%	6,228
European (non-Finnish)grpmax	0.0108%	9,252
African / African-American	0.00401%	24,925

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His74=
Coding: c.222T>C
MANE Select: NM_001042432
dbSNP: rs201225986
Type: single nucleotide variant
Location: chr16:28489290 (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

Also linked: neuronal ceroid lipofuscinosis 3

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-his74 (accessed [today's date]).

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