Is PLAA p.Ser765Tyr (c.2294C>A) pathogenic?

PLAA p.Ser765Tyr (c.2294C>A) is classified Uncertain significance in PLAA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-22). AlphaMissense: likely pathogenic (0.8643); Very rare (popmax 0.00934%, afr); Associated with Inborn genetic diseases.

What condition is associated with PLAA p.Ser765Tyr (c.2294C>A)?

PLAA p.Ser765Tyr (c.2294C>A) is associated with Inborn genetic diseases (ClinVar).

How common is PLAA p.Ser765Tyr (c.2294C>A) in the general population?

PLAA p.Ser765Tyr (c.2294C>A) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about PLAA p.Ser765Tyr (c.2294C>A)?

AlphaMissense predicts likely pathogenic (score 0.8643) — an in-silico prediction, not a clinical call.

PLAA p.Ser765Tyr

c.2294C>A · rs777597597 · VCV1370231

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8643	likely pathogenic
REVEL	0.505	indeterminate
SaProt	LLR -8.14	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 42 kb · p 0.094 · regional, not allelic
Overall
CADD	27.0	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

Grpmax group 0.00934% African / African-American · 7/74,932 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00186% 30/1,613,842 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,705
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.00178%	56,183

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.Ser765Tyr
Coding: c.2294C>A
MANE Select: NM_001031689
dbSNP: rs777597597
Type: single nucleotide variant
Location: chr9:26905605 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.87 · 5 PDB
Residue 765: an α-helix; the pul domain

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.Ser765= Likely benign ★★ same residue
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

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-ser765tyr (accessed [today's date]).

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