Is FH p.Met1Val (c.1A>G) pathogenic?

FH p.Met1Val (c.1A>G) is classified Conflicting classifications of pathogenicity in FH (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-04-11). Very rare (popmax 0.00492%, eas); Associated with fumaric aciduria.

What condition is associated with FH p.Met1Val (c.1A>G)?

FH p.Met1Val (c.1A>G) is associated with fumaric aciduria, hereditary leiomyomatosis and renal cell cancer, hereditary neoplastic syndrome (ClinVar).

How common is FH p.Met1Val (c.1A>G) in the general population?

FH p.Met1Val (c.1A>G) is very rare (popmax 0.00492%, eas) (gnomAD).

How is Fumaric aciduria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

FH p.Met1Val

c.1A>G · rs776806414 · VCV237113

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00492%, eas)

Conditions

fumaric aciduria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.675	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00492% East Asian · 2/40,638 alleles

Filtering AF 0.000816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000305%

Overall 0.000324% 5/1,543,456 alleles · very rare exomes 3/1,391,288 · genomes 2/152,168 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00492%	20,319
African / African-American	0.00276%	36,278
European (non-Finnish)	8.75e-05%	1,143,440

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: FH
Protein: p.Met1Val
Coding: c.1A>G
MANE Select: NM_000143
dbSNP: rs776806414
Type: single nucleotide variant
Location: chr1:241519722 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB

Full FH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

fumaric aciduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary leiomyomatosis and renal cell cancer hereditary neoplastic syndrome

For Fumaric aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

FH p.Met1Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Met1Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Met1Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Met1Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Met1Ile Likely pathogenic ★★ same residue
FH c.1108+1G>A Pathogenic ★★ same condition
FH c.1108+1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1236+1G>A 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/fh-p-met1val (accessed [today's date]).

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