Is CSRNP2 p.Pro505Leu (c.1514C>T) pathogenic?

CSRNP2 p.Pro505Leu (c.1514C>T) is classified Uncertain significance in CSRNP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely benign (0.076); Ultra-rare (popmax 0.0187%, sas).

How common is CSRNP2 p.Pro505Leu (c.1514C>T) in the general population?

CSRNP2 p.Pro505Leu (c.1514C>T) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

What do computational predictors say about CSRNP2 p.Pro505Leu (c.1514C>T)?

AlphaMissense predicts likely benign (score 0.076) — an in-silico prediction, not a clinical call.

CSRNP2 p.Pro505Leu

c.1514C>T · rs201394453 · VCV3078372

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.076 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.076	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -6.30	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 5	GERP 0.26, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 794 bp · p 0.0097 · regional, not allelic
Overall
CADD	21.1	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 0.0187% South Asian · 17/91,074 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00211% 34/1,614,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,357
Middle Eastern	0.0165%	6,062
East Asian	0.0134%	7,478
African / African-American	0.00533%	18,755
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)	0.000254%	393,335

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.Pro505Leu
Coding: c.1514C>T
MANE Select: NM_030809
dbSNP: rs201394453
Type: single nucleotide variant
Location: chr12:51063864 (GRCh38)
Gene constraint: LOEUF 0.466 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.02
Residue 505: 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-pro505leu (accessed [today's date]).

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