Is FH p.Phe50Ser (c.149T>C) pathogenic?

FH p.Phe50Ser (c.149T>C) is classified Uncertain significance in FH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-27). AlphaMissense: ambiguous (0.3406); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Phe50Ser (c.149T>C)?

FH p.Phe50Ser (c.149T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is FH p.Phe50Ser (c.149T>C) in the general population?

FH p.Phe50Ser (c.149T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about FH p.Phe50Ser (c.149T>C)?

AlphaMissense predicts ambiguous (score 0.3406) — an in-silico prediction, not a clinical call.

FH p.Phe50Ser

c.149T>C · VCV4257320

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3406 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3406	ambiguous
REVEL	0.622	indeterminate
SaProt	LLR -7.09	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP -0.94, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 6,014 bp · p 0.17 · regional, not allelic
Overall
CADD	21.8	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.2e-05% 1/1,614,124 alleles · very rare exomes 1/1,461,792 · genomes 0/152,332 · joint denominator

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.Phe50Ser
Coding: c.149T>C
MANE Select: NM_000143
Type: single nucleotide variant
Location: chr1:241517300 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 50: a β-strand

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

Similar variants

FH p.Phe50Leu Uncertain significance ★★ ⚠ same residue
FH p.Phe50= Benign/Likely benign ★★ same residue
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
FH c.1237-1G>T Likely pathogenic ★★ same condition
FH c.1390+1G>T 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-phe50ser (accessed [today's date]).

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