Is FAH p.Val91Met (c.271G>A) pathogenic?

FAH p.Val91Met (c.271G>A) is classified Uncertain significance in FAH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-20). AlphaMissense: likely benign (0.1323); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with FAH p.Val91Met (c.271G>A)?

FAH p.Val91Met (c.271G>A) is associated with Inborn genetic diseases (ClinVar).

How common is FAH p.Val91Met (c.271G>A) in the general population?

FAH p.Val91Met (c.271G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about FAH p.Val91Met (c.271G>A)?

AlphaMissense predicts likely benign (score 0.1323) — an in-silico prediction, not a clinical call.

FAH p.Val91Met

c.271G>A · rs374371839 · VCV596939

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1323 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1323	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -7.66	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.93, phastCons 0.007
Regional constraint	o/e 0.91	unconstrained · MANE · 33 kb · p 0.029 · regional, not allelic
Overall
CADD	16.95	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

Grpmax group 0.00267% African / African-American · 2/74,948 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000558% 9/1,614,136 alleles · very rare exomes 7/1,461,884 · genomes 2/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,474
European (non-Finnish)	0.000593%	168,577

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.Val91Met
Coding: c.271G>A
MANE Select: NM_000137
dbSNP: rs374371839
Type: single nucleotide variant
Location: chr15:80159834 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FAH p.Val91Gly Uncertain significance ★ ⚠ same residue
FAH p.Gly343Trp Pathogenic/Likely pathogenic ★★ same condition
FAH c.82-3T>C Uncertain significance ★★ same condition
FAH p.Arg131Gln Uncertain significance ★★ ⚠ same condition
FAH p.Arg162His Uncertain significance ★★ ⚠ same condition
FAH p.Arg341Gln Uncertain significance ★★ ⚠ same condition
FAH p.Arg97Ser Uncertain significance ★★ ⚠ same condition
FAH p.Asn136Ser Uncertain significance ★★ ⚠ 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-val91met (accessed [today's date]).

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