Is FH p.Ala103= (c.309C>T) pathogenic?

FH p.Ala103= (c.309C>T) is classified Benign in FH (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-02-04). Common (popmax 9.59%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Ala103= (c.309C>T)?

FH p.Ala103= (c.309C>T) is associated with hereditary neoplastic syndrome, hereditary leiomyomatosis and renal cell cancer, fumaric aciduria (ClinVar).

FH p.Ala103=

Q: How common is FH p.Ala103= (c.309C>T) in the general population?

FH p.Ala103= (c.309C>T) is common (popmax 9.59%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.309C>T · rs10926501 · VCV137373

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

gnomAD v4.1

Common

common (popmax 9.59%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.29	phastCons 0.37
Overall
CADD	10.55	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.59% African / African-American · 7,191/74,980 alleles

Filtering AF 9.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.33%

Overall 0.497% 8,025/1,613,946 alleles · common exomes 3,962/1,461,798 · genomes 4,063/152,148 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.59%	10
Remaining individualsnot grpmax-eligible	0.574%	174
Admixed American	0.56%	179
Middle Eastern	0.231%	433
South Asian	0.00988%	10,119
European (non-Finnish)	0.00949%	10,535
East Asian	0.00669%	14,957
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600

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.Ala103=
Coding: c.309C>T
MANE Select: NM_000143
dbSNP: rs10926501
Type: single nucleotide variant
Location: chr1:241513672 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 103: an α-helix

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary leiomyomatosis and renal cell cancer fumaric aciduria

Similar variants

FH p.Ala103Val Uncertain significance ★★ ⚠ same residue
FH p.Ala103Ser Uncertain significance ★ ⚠ same residue
FH p.Ala103Thr Uncertain significance ★ ⚠ 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
FH c.1236+1G>C Pathogenic ★★ same condition
FH c.1236+2T>G 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-ala103 (accessed [today's date]).

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