Is PLAA p.Asp49His (c.145G>C) pathogenic?

PLAA p.Asp49His (c.145G>C) is classified Uncertain significance in PLAA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-18). AlphaMissense: likely benign (0.1435); Very rare (popmax 0.00116%, sas).

How common is PLAA p.Asp49His (c.145G>C) in the general population?

PLAA p.Asp49His (c.145G>C) is very rare (popmax 0.00116%, sas) (gnomAD).

What do computational predictors say about PLAA p.Asp49His (c.145G>C)?

AlphaMissense predicts likely benign (score 0.1435) — an in-silico prediction, not a clinical call.

PLAA p.Asp49His

c.145G>C · VCV4737150

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1435 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00116%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1435	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -6.92	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 1.1	GERP 1.8, phastCons 0.52
Regional constraint	o/e 0.95	unconstrained · MANE · 42 kb · p 0.094 · regional, not allelic
Overall
CADD	22.1	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 0.00116% South Asian · 1/86,120 alleles

Filtering AF 0.00055% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000434%

Overall 0.000822% 13/1,581,010 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00116%	86,120
European (non-Finnish)	0.00103%	97,024

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: PLAA
Protein: p.Asp49His
Coding: c.145G>C
MANE Select: NM_001031689
Type: single nucleotide variant
Location: chr9:26946901 (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

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-asp49his (accessed [today's date]).

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