Is PLAA p.Ser423Cys (c.1267A>T) pathogenic?

PLAA p.Ser423Cys (c.1267A>T) is classified Uncertain significance in PLAA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-19). AlphaMissense: likely benign (0.1051); Absent from gnomAD v4.1.

How common is PLAA p.Ser423Cys (c.1267A>T) in the general population?

PLAA p.Ser423Cys (c.1267A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PLAA p.Ser423Cys (c.1267A>T)?

AlphaMissense predicts likely benign (score 0.1051) — an in-silico prediction, not a clinical call.

PLAA p.Ser423Cys

c.1267A>T · rs2489187055 · VCV2008406

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1051 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1051	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -11.07	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 42 kb · p 0.094 · regional, not allelic
Overall
CADD	23.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PLAA
Protein: p.Ser423Cys
Coding: c.1267A>T
MANE Select: NM_001031689
dbSNP: rs2489187055
Type: single nucleotide variant
Location: chr9:26919460 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.87 · 5 PDB
Residue 423: the pfu domain

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

Similar variants

PLAA p.Arg524Ter Likely pathogenic ★★ same type
PLAA p.Ala156Val Uncertain significance ★★ ⚠ same type
PLAA p.Ala264Thr Uncertain significance ★★ ⚠ same type
PLAA p.Ala271Val Uncertain significance ★★ ⚠ same type
PLAA p.Arg268Gln Uncertain significance ★★ ⚠ same type
PLAA p.Arg373Thr Uncertain significance ★★ ⚠ same type
PLAA p.Arg499Cys Uncertain significance ★★ ⚠ same type
PLAA p.Arg7Ser 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/plaa-p-ser423cys (accessed [today's date]).

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