Is CSRNP2 p.Arg194His (c.581G>A) pathogenic?

CSRNP2 p.Arg194His (c.581G>A) is classified Uncertain significance in CSRNP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-15). AlphaMissense: likely pathogenic (0.6156); Ultra-rare (popmax 0.0107%, afr).

How common is CSRNP2 p.Arg194His (c.581G>A) in the general population?

CSRNP2 p.Arg194His (c.581G>A) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about CSRNP2 p.Arg194His (c.581G>A)?

AlphaMissense predicts likely pathogenic (score 0.6156) — an in-silico prediction, not a clinical call.

CSRNP2 p.Arg194His

c.581G>A · VCV3497925

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6156 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6156	likely pathogenic
REVEL	0.244	benign-leaning
SaProt	LLR -5.66	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 12 kb · p 3.3e-17 · regional, not allelic
Overall
CADD	32.0	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 0.0107% African / African-American · 8/74,936 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00118% 19/1,614,110 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,367
European (non-Finnish)	0.000932%	107,276

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.Arg194His
Coding: c.581G>A
MANE Select: NM_030809
Type: single nucleotide variant
Location: chr12:51067800 (GRCh38)
Gene constraint: LOEUF 0.466 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.02

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.Arg218Gln Uncertain significance ★ ⚠ same type
CSRNP2 p.Arg282Gln Uncertain significance ★ ⚠ same type
CSRNP2 p.Arg286Leu Uncertain significance ★ ⚠ same type
CSRNP2 p.Arg335Gln 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-arg194his (accessed [today's date]).

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