Is PLAA p.Tyr477His (c.1429T>C) pathogenic?

PLAA p.Tyr477His (c.1429T>C) is classified Uncertain significance in PLAA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-27). AlphaMissense: likely pathogenic (0.9289); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PLAA p.Tyr477His (c.1429T>C)?

PLAA p.Tyr477His (c.1429T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PLAA p.Tyr477His (c.1429T>C) in the general population?

PLAA p.Tyr477His (c.1429T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PLAA p.Tyr477His (c.1429T>C)?

AlphaMissense predicts likely pathogenic (score 0.9289) — an in-silico prediction, not a clinical call.

PLAA p.Tyr477His

c.1429T>C · rs1824589683 · VCV2196845

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9289 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9289	likely pathogenic
REVEL	0.339	indeterminate
SaProt	LLR -12.25	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 42 kb · p 0.094 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Tyr477His
Coding: c.1429T>C
MANE Select: NM_001031689
dbSNP: rs1824589683
Type: single nucleotide variant
Location: chr9:26917154 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.87 · 5 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLAA p.Ala271Val Uncertain significance ★★ ⚠ same condition
PLAA p.Arg268Gln Uncertain significance ★★ ⚠ same condition
PLAA p.Arg373Thr Uncertain significance ★★ ⚠ same condition
PLAA p.Arg499Cys Uncertain significance ★★ ⚠ same condition
PLAA p.Arg7Ser Uncertain significance ★★ ⚠ same condition
PLAA p.Asn410Ser Uncertain significance ★★ ⚠ same condition
PLAA p.Asn520Ser Uncertain significance ★★ ⚠ same condition
PLAA p.Asn66Ser Uncertain significance ★★ ⚠ same condition

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-tyr477his (accessed [today's date]).

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