Is FH p.Val436= (c.1308G>A) pathogenic?

FH p.Val436= (c.1308G>A) is classified Benign/Likely benign in FH (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-31). Rare (popmax 0.17%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Val436= (c.1308G>A)?

FH p.Val436= (c.1308G>A) is associated with hereditary neoplastic syndrome, hereditary leiomyomatosis and renal cell cancer (ClinVar).

How common is FH p.Val436= (c.1308G>A) in the general population?

FH p.Val436= (c.1308G>A) is rare (popmax 0.17%, sas) (gnomAD).

FH p.Val436=

c.1308G>A · rs201535626 · VCV413607

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.17%, sas)

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 -2.8	GERP -5.2
Overall
CADD	3.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.17% South Asian · 155/91,050 alleles

Filtering AF 0.148% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.14%

Overall 0.0106% 171/1,613,642 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.17%	587
Middle Eastern	0.033%	3,027
Remaining individualsnot grpmax-eligible	0.0064%	15,624
European (non-Finnish)	0.000848%	117,990

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.Val436=
Coding: c.1308G>A
MANE Select: NM_000143
dbSNP: rs201535626
Type: single nucleotide variant
Location: chr1:241500519 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 436: 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

Similar variants

FH p.Val436Met Uncertain significance ★★ ⚠ same residue
FH p.Val436Ala Uncertain significance ★ ⚠ same residue
FH p.Val436Glu Uncertain significance ★ ⚠ same residue
FH p.Val436Leu 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

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-val436 (accessed [today's date]).

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