Is PAH p.Lys74= (c.222A>G) pathogenic?

PAH p.Lys74= (c.222A>G) is classified Uncertain significance in PAH (ClinVar, Expert panel, 3 submitters; last evaluated 2023-07-23). Ultra-rare (popmax 0.0333%, afr); Associated with phenylketonuria.

What condition is associated with PAH p.Lys74= (c.222A>G)?

PAH p.Lys74= (c.222A>G) is associated with phenylketonuria (ClinVar).

How common is PAH p.Lys74= (c.222A>G) in the general population?

PAH p.Lys74= (c.222A>G) is ultra-rare (popmax 0.0333%, afr) (gnomAD).

How is Phenylketonuria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PAH p.Lys74=

c.222A>G · rs374797155 · VCV991624

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, afr)

Conditions

phenylketonuria

ClinGen expert panel

Uncertain Significance — Phenylketonuria VCEP (phenylketonuria).

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.29	GERP -1.4, phastCons 1
Overall
CADD	7.791	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% African / African-American · 25/75,052 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00204% 33/1,614,014 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0333%	3,002
Remaining individualsnot grpmax-eligible	0.0048%	20,834
Admixed American	0.00167%	60,018
South Asian	0.0011%	91,074
European (non-Finnish)	0.000254%	393,294

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: PAH
Protein: p.Lys74=
Coding: c.222A>G
MANE Select: NM_000277
dbSNP: rs374797155
Type: single nucleotide variant
Location: chr12:102894865 (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 74: the act domain

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

Disease context

phenylketonuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Phenylketonuria (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy
Prevalence: 1-9 / 100 000 (France)

Similar variants

PAH c.1065+1G>A Likely pathogenic ★★★ same condition
PAH c.1065+1G>T Likely pathogenic ★★★ same condition
PAH c.1065+3A>G Likely pathogenic ★★★ same condition
PAH c.1066-11G>A Pathogenic ★★★ same condition
PAH c.1066-14C>G Likely pathogenic ★★★ same condition
PAH c.1066-1G>A Pathogenic ★★★ same condition
PAH c.1066-1G>C Pathogenic ★★★ same condition
PAH c.1066-1G>T Pathogenic ★★★ 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/pah-p-lys74 (accessed [today's date]).

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