Is FAH p.Pro249Ser (c.745C>T) pathogenic?

FAH p.Pro249Ser (c.745C>T) is classified Likely pathogenic in FAH (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-28). AlphaMissense: likely pathogenic (0.8839); Absent from gnomAD v4.1; Associated with tyrosinemia type I.

What condition is associated with FAH p.Pro249Ser (c.745C>T)?

FAH p.Pro249Ser (c.745C>T) is associated with tyrosinemia type I (ClinVar).

How common is FAH p.Pro249Ser (c.745C>T) in the general population?

FAH p.Pro249Ser (c.745C>T) is absent from gnomAD v4.1 (gnomAD).

How is Tyrosinemia type 1 inherited?

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

What do computational predictors say about FAH p.Pro249Ser (c.745C>T)?

AlphaMissense predicts likely pathogenic (score 0.8839) — an in-silico prediction, not a clinical call.

FAH p.Pro249Ser

c.745C>T · rs1595894742 · VCV803109

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8839 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tyrosinemia type I

Computational evidence

Protein change
AlphaMissense	0.8839	likely pathogenic ✓ concordant with ClinVar
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -13.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 33 kb · p 0.029 · regional, not allelic
Overall
CADD	27.5	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: FAH
Protein: p.Pro249Ser
Coding: c.745C>T
MANE Select: NM_000137
dbSNP: rs1595894742
Type: single nucleotide variant
Location: chr15:80173052 (GRCh38)
Gene constraint: LOEUF 1.067 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 98.06 · 8 PDB
Residue 249: a UniProt-annotated variant site (in tyrsn1)

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

Disease context

tyrosinemia type I — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Tyrosinemia type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

FAH p.Pro249Thr Pathogenic/Likely pathogenic ★★ same residue
FAH p.Pro249= Likely benign ★ same residue
FAH p.Pro249fs Pathogenic ★★ same residue
FAH c.1062+5G>A Pathogenic/Likely pathogenic ★★ same condition
FAH c.1180+1G>A Pathogenic ★★ same condition
FAH c.192+1G>A Likely pathogenic ★★ same condition
FAH c.192+1G>T Pathogenic/Likely pathogenic ★★ same condition
FAH c.193-2A>G Likely 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/fah-p-pro249ser (accessed [today's date]).

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