Is FAH p.Val21Phe (c.61G>T) pathogenic?

FAH p.Val21Phe (c.61G>T) is classified Conflicting classifications of pathogenicity in FAH (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.5641); No allele count reported in gnomAD v4.1 (AN 1,613,696); Associated with tyrosinemia type I.

What condition is associated with FAH p.Val21Phe (c.61G>T)?

FAH p.Val21Phe (c.61G>T) is associated with tyrosinemia type I (ClinVar).

How common is FAH p.Val21Phe (c.61G>T) in the general population?

FAH p.Val21Phe (c.61G>T) is no allele count reported in gnomAD v4.1 (AN 1,613,696) (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.Val21Phe (c.61G>T)?

AlphaMissense predicts likely pathogenic (score 0.5641) — an in-silico prediction, not a clinical call.

FAH p.Val21Phe

c.61G>T · rs2041065908 · VCV1685807

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5641 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,696)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tyrosinemia type I

Computational evidence

Protein change
AlphaMissense	0.5641	likely pathogenic
REVEL	0.806	moderately pathogenic-leaning
SaProt	LLR -14.73	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 4.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 33 kb · p 0.029 · regional, not allelic
Overall
CADD	27.2	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

No allele count reported in gnomAD v4.1 (AN 1,613,696). 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.Val21Phe
Coding: c.61G>T
MANE Select: NM_000137
dbSNP: rs2041065908
Type: single nucleotide variant
Location: chr15:80153115 (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 p.Val21= Likely benign ★ 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
FAH c.314+1G>A Likely pathogenic ★★ same condition
FAH c.315-3C>G Pathogenic/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-val21phe (accessed [today's date]).

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