Is IL31RA p.Pro43= (c.129C>T) pathogenic?

IL31RA p.Pro43= (c.129C>T) is classified Benign in IL31RA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-19). Common (popmax 78.1%, sas) — too common for a highly-penetrant pathogenic allele; Associated with amyloidosis, primary localized cutaneous, 2.

What condition is associated with IL31RA p.Pro43= (c.129C>T)?

IL31RA p.Pro43= (c.129C>T) is associated with amyloidosis, primary localized cutaneous, 2 (ClinVar).

IL31RA p.Pro43=

Q: How common is IL31RA p.Pro43= (c.129C>T) in the general population?

IL31RA p.Pro43= (c.129C>T) is common (popmax 78.1%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Familial primary localized cutaneous amyloidosis inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.129C>T · rs1009639 · VCV1300053

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 78.1%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

amyloidosis, primary localized cutaneous, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -2.9
Overall
CADD	0.852	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 78.1% South Asian · 71,057/91,034 alleles

Filtering AF 77.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 77.4%

Overall 71.7% 1,155,611/1,612,148 alleles · common exomes 1,049,850/1,460,080 · genomes 105,761/152,068 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	78.1%	1
Finnishnot grpmax-eligible	77%	1
Middle Eastern	76.2%	1
Ashkenazi Jewishnot grpmax-eligible	74.4%	1
European (non-Finnish)	73.2%	1
Amishnot grpmax-eligible	72.2%	1
Remaining individualsnot grpmax-eligible	71.7%	1
African / African-American	66.8%	1
East Asian	49.2%	2
Admixed American	46.9%	2

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: IL31RA
Protein: p.Pro43=
Coding: c.129C>T
MANE Select: NM_139017
dbSNP: rs1009639
Type: single nucleotide variant
Location: chr5:55859574 (GRCh38)
Gene constraint: LOEUF 0.951 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.34 · 2 PDB
Residue 43: a β-strand; the fibronectin type-iii 1 domain

Full IL31RA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

amyloidosis, primary localized cutaneous, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial primary localized cutaneous amyloidosis (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

IL31RA p.Ala715Thr Uncertain significance ★★ same condition
IL31RA p.Ser443Thr Uncertain significance ★★ same condition
IL31RA c.1819-26T>G Benign ★★ same condition
IL31RA c.606+29A>T Benign ★★ same condition
IL31RA p.Gly483= Benign ★★ same condition
IL31RA c.1070-3C>G Uncertain significance ★ same condition
IL31RA p.Ser521Phe Pathogenic same condition
IL31RA c.773-9T>C Benign ★★ 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/il31ra-p-pro43 (accessed [today's date]).

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