Is FAH p.Ala77Val (c.230C>T) pathogenic?

FAH p.Ala77Val (c.230C>T) is classified Uncertain significance in FAH (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-04-22). AlphaMissense: likely benign (0.1346); Very rare (popmax 8.47e-05%, nfe); Associated with tyrosinemia type I.

What condition is associated with FAH p.Ala77Val (c.230C>T)?

FAH p.Ala77Val (c.230C>T) is associated with tyrosinemia type I (ClinVar).

How common is FAH p.Ala77Val (c.230C>T) in the general population?

FAH p.Ala77Val (c.230C>T) is very rare (popmax 8.47e-05%, nfe) (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.Ala77Val (c.230C>T)?

AlphaMissense predicts likely benign (score 0.1346) — an in-silico prediction, not a clinical call.

FAH p.Ala77Val

c.230C>T · VCV4067846

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1346 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tyrosinemia type I

Computational evidence

Protein change
AlphaMissense	0.1346	likely benign
REVEL	0.704	pathogenic-leaning
SaProt	LLR -11.38	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 33 kb · p 0.029 · regional, not allelic
Overall
CADD	23.1	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 8.47e-05% European (non-Finnish) · 1/1,180,042 alleles

Overall 6.84e-05% 1/1,461,894 alleles · very rare

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: FAH
Protein: p.Ala77Val
Coding: c.230C>T
MANE Select: NM_000137
Type: single nucleotide variant
Location: chr15:80159793 (GRCh38)
Gene constraint: LOEUF 1.067 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 98.06 · 8 PDB

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 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
FAH c.314+1G>A Likely pathogenic ★★ same condition
FAH c.315-3C>G Pathogenic/Likely pathogenic ★★ same condition
FAH c.365-2A>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-ala77val (accessed [today's date]).

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