Is CSN2 p.Ser25Arg (c.73A>C) pathogenic?

CSN2 p.Ser25Arg (c.73A>C) is classified Uncertain significance in CSN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-13). AlphaMissense: ambiguous (0.4489); Very rare (popmax 0.00322%, nfe).

How common is CSN2 p.Ser25Arg (c.73A>C) in the general population?

CSN2 p.Ser25Arg (c.73A>C) is very rare (popmax 0.00322%, nfe) (gnomAD).

What do computational predictors say about CSN2 p.Ser25Arg (c.73A>C)?

AlphaMissense predicts ambiguous (score 0.4489) — an in-silico prediction, not a clinical call.

CSN2 p.Ser25Arg

c.73A>C · rs745520012 · VCV2461588

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4489 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4489	ambiguous · top 4% in CSN2
REVEL	0.1	moderately benign-leaning
SaProt	LLR -9.82	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.26	unconstrained · MANE · 4,642 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	21.1	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 0.00322% European (non-Finnish) · 38/1,178,696 alleles

Filtering AF 0.0024% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00267% 39/1,459,764 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,018
Remaining individualsnot grpmax-eligible	0.0016%	62,384

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.Ser25Arg
Coding: c.73A>C
MANE Select: NM_001891
dbSNP: rs745520012
Type: single nucleotide variant
Location: chr4:69960058 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.09
Residue 25: a modified residue (phosphoserine; in form 1-p, form 2-p, form 3-p, form 4-p and form 5-p)

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-ser25arg (accessed [today's date]).

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