Is CSRNP2 p.Glu538Gln (c.1612G>C) pathogenic?

CSRNP2 p.Glu538Gln (c.1612G>C) is classified Uncertain significance in CSRNP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). AlphaMissense: likely benign (0.0833); Rare (popmax 0.105%, nfe).

How common is CSRNP2 p.Glu538Gln (c.1612G>C) in the general population?

CSRNP2 p.Glu538Gln (c.1612G>C) is rare (popmax 0.105%, nfe) (gnomAD).

What do computational predictors say about CSRNP2 p.Glu538Gln (c.1612G>C)?

AlphaMissense predicts likely benign (score 0.0833) — an in-silico prediction, not a clinical call.

CSRNP2 p.Glu538Gln

c.1612G>C · rs139339223 · VCV2401213

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0833 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0833	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -6.26	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 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 794 bp · p 0.0097 · regional, not allelic
Overall
CADD	22.3	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 0.105% European (non-Finnish) · 1,221/1,158,736 alleles

Filtering AF 0.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0984%

Overall 0.0811% 1,275/1,571,794 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.105%	949
Remaining individualsnot grpmax-eligible	0.0479%	2,087
African / African-American	0.0258%	3,870
Finnishnot grpmax-eligible	0.0064%	15,627
Admixed American	0.00374%	26,720

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: CSRNP2
Protein: p.Glu538Gln
Coding: c.1612G>C
MANE Select: NM_030809
dbSNP: rs139339223
Type: single nucleotide variant
Location: chr12:51063766 (GRCh38)
Gene constraint: LOEUF 0.466 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.02
Residue 538: the 'disordered' region

Full CSRNP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSRNP2 p.Ala255Val Uncertain significance ★ ⚠ same type
CSRNP2 p.Ala289Thr Uncertain significance ★ ⚠ same type
CSRNP2 p.Arg123Cys Uncertain significance ★ ⚠ same type
CSRNP2 p.Arg184Gln Uncertain significance ★ ⚠ same type
CSRNP2 p.Arg194His Uncertain significance ★ ⚠ same type
CSRNP2 p.Arg218Gln Uncertain significance ★ ⚠ same type
CSRNP2 p.Arg282Gln Uncertain significance ★ ⚠ same type
CSRNP2 p.Arg286Leu 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/csrnp2-p-glu538gln (accessed [today's date]).

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