Is PAH p.Pro89Arg (c.266C>G) pathogenic?

PAH p.Pro89Arg (c.266C>G) is classified Uncertain significance in PAH (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-20). AlphaMissense: likely benign (0.1223); Absent from gnomAD v4.1.

How common is PAH p.Pro89Arg (c.266C>G) in the general population?

PAH p.Pro89Arg (c.266C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PAH p.Pro89Arg (c.266C>G)?

AlphaMissense predicts likely benign (score 0.1223) — an in-silico prediction, not a clinical call.

PAH p.Pro89Arg

c.266C>G · VCV4689197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1223 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1223	likely benign
REVEL	0.518	indeterminate
SaProt	LLR -10.77	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic
Overall
CADD	20.3	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: PAH
Protein: p.Pro89Arg
Coding: c.266C>G
MANE Select: NM_000277
Type: single nucleotide variant
Location: chr12:102894821 (GRCh38)
Gene constraint: LOEUF 1.265 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.04 · 21 PDB
Residue 89: the act domain; an α-helix

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

Similar variants

PAH p.Pro89Ser Pathogenic/Likely pathogenic ★★ ⚠ same residue
PAH p.Pro89Thr Likely pathogenic ★★ ⚠ same residue
PAH c.1065+1G>A Likely pathogenic ★★★ same type
PAH c.1065+1G>T Likely pathogenic ★★★ same type
PAH c.1065+3A>G Likely pathogenic ★★★ same type
PAH c.1066-11G>A Pathogenic ★★★ same type
PAH c.1066-14C>G Likely pathogenic ★★★ same type
PAH c.1066-1G>A Pathogenic ★★★ 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/pah-p-pro89arg (accessed [today's date]).

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