Is FAH p.Ser56Phe (c.167C>T) pathogenic?

FAH p.Ser56Phe (c.167C>T) is classified Uncertain significance in FAH (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.1806); Very rare (popmax 0.00017%, nfe); Associated with tyrosinemia type I.

What condition is associated with FAH p.Ser56Phe (c.167C>T)?

FAH p.Ser56Phe (c.167C>T) is associated with tyrosinemia type I (ClinVar).

How common is FAH p.Ser56Phe (c.167C>T) in the general population?

FAH p.Ser56Phe (c.167C>T) is very rare (popmax 0.00017%, 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.Ser56Phe (c.167C>T)?

AlphaMissense predicts likely benign (score 0.1806) — an in-silico prediction, not a clinical call.

FAH p.Ser56Phe

c.167C>T · rs770312290 · VCV317208

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1806 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

tyrosinemia type I

Computational evidence

Protein change
AlphaMissense	0.1806	likely benign
REVEL	0.557	indeterminate
SaProt	LLR -11.04	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	GERP -0.7, phastCons 0.05
Regional constraint	o/e 0.91	unconstrained · MANE · 33 kb · p 0.029 · regional, not allelic
Overall
CADD	21.9	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 0.00017% European (non-Finnish) · 2/1,179,706 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,862 alleles · very rare exomes 2/1,461,526 · genomes 0/152,336 · joint denominator

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.Ser56Phe
Coding: c.167C>T
MANE Select: NM_000137
dbSNP: rs770312290
Type: single nucleotide variant
Location: chr15:80158145 (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-ser56phe (accessed [today's date]).

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