Is FAH p.Thr331Ala (c.991A>G) pathogenic?

FAH p.Thr331Ala (c.991A>G) is classified Uncertain significance in FAH (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-01). AlphaMissense: likely benign (0.074); Absent from gnomAD v4.1; Associated with tyrosinemia type I.

What condition is associated with FAH p.Thr331Ala (c.991A>G)?

FAH p.Thr331Ala (c.991A>G) is associated with tyrosinemia type I (ClinVar).

How common is FAH p.Thr331Ala (c.991A>G) in the general population?

FAH p.Thr331Ala (c.991A>G) 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.Thr331Ala (c.991A>G)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

FAH p.Thr331Ala

c.991A>G · rs1595897330 · VCV2441334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,610,982)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tyrosinemia type I

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -4.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -1.6
Regional constraint	o/e 0.91	unconstrained · MANE · 33 kb · p 0.029 · regional, not allelic
Overall
CADD	5.243	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,610,982). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: FAH
Protein: p.Thr331Ala
Coding: c.991A>G
MANE Select: NM_000137
dbSNP: rs1595897330
Type: single nucleotide variant
Location: chr15:80180154 (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
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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-thr331ala (accessed [today's date]).

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