Is PIR p.Pro142Ser (c.424C>T) pathogenic?

PIR p.Pro142Ser (c.424C>T) is classified Uncertain significance in PIR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-20). AlphaMissense: likely benign (0.1743); Very rare (popmax 0.00351%, sas).

How common is PIR p.Pro142Ser (c.424C>T) in the general population?

PIR p.Pro142Ser (c.424C>T) is very rare (popmax 0.00351%, sas) (gnomAD).

What do computational predictors say about PIR p.Pro142Ser (c.424C>T)?

AlphaMissense predicts likely benign (score 0.1743) — an in-silico prediction, not a clinical call.

PIR p.Pro142Ser

c.424C>T · rs1376925618 · VCV2337699

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1743 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00351%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1743	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -9.18	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 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 106 kb · p 0.98 · regional, not allelic
Overall
CADD	16.63	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 0.00351% South Asian · 2/56,946 alleles

Filtering AF 0.000583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000218%

Overall 0.000182% 2/1,096,929 alleles · very rare

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: PIR
Protein: p.Pro142Ser
Coding: c.424C>T
MANE Select: NM_001018109
dbSNP: rs1376925618
Type: single nucleotide variant
Location: chrX:15455904 (GRCh38)
Structure: AlphaFold pLDDT 97.11 · 13 PDB

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

Similar variants

PIR p.Asp232Asn Benign ★★ same type
PIR p.Val228Ala Benign ★★ same type
PIR p.Ala274Thr Uncertain significance ★ ⚠ same type
PIR p.Arg14Gln Uncertain significance ★ ⚠ same type
PIR p.Arg25Gln Uncertain significance ★ ⚠ same type
PIR p.Arg97Gln Uncertain significance ★ ⚠ same type
PIR p.Asn273Asp Uncertain significance ★ ⚠ same type
PIR p.Asp145Asn 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/pir-p-pro142ser (accessed [today's date]).

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