Is CSN2 p.Leu4Phe (c.10C>T) pathogenic?

CSN2 p.Leu4Phe (c.10C>T) is classified Uncertain significance in CSN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.0663); Very rare (popmax 0.00334%, amr).

How common is CSN2 p.Leu4Phe (c.10C>T) in the general population?

CSN2 p.Leu4Phe (c.10C>T) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about CSN2 p.Leu4Phe (c.10C>T)?

AlphaMissense predicts likely benign (score 0.0663) — an in-silico prediction, not a clinical call.

CSN2 p.Leu4Phe

c.10C>T · VCV4007571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0663 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0663	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.37	GERP -3.5
Regional constraint	o/e 1.26	unconstrained · MANE · 4,642 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	0.152	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 0.00334% Admixed American · 2/59,822 alleles

Filtering AF 0.000555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000208%

Overall 0.000806% 13/1,612,486 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,912
Admixed Americangrpmax	0.00334%	29,911
European (non-Finnish)	0.000339%	294,774

Remaining individuals 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: CSN2
Protein: p.Leu4Phe
Coding: c.10C>T
MANE Select: NM_001891
Type: single nucleotide variant
Location: chr4:69960986 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.09

Full CSN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSN2 p.Ala162Thr Uncertain significance ★ ⚠ same type
CSN2 p.Ala190Gly Uncertain significance ★ ⚠ same type
CSN2 p.Ala85Pro Uncertain significance ★ ⚠ same type
CSN2 p.Arg189Lys Uncertain significance ★ ⚠ same type
CSN2 p.Asp106Asn Uncertain significance ★ ⚠ same type
CSN2 p.Gln194Arg Uncertain significance ★ ⚠ same type
CSN2 p.Glu20Asp Uncertain significance ★ ⚠ same type
CSN2 p.Gly112Arg Uncertain significance ★ ⚠ 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/csn2-p-leu4phe (accessed [today's date]).

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