Is FH p.Pro137Ser (c.409C>T) pathogenic?

FH p.Pro137Ser (c.409C>T) is classified Uncertain significance in FH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-29). AlphaMissense: likely pathogenic (0.9478); Absent from gnomAD v4.1.

How common is FH p.Pro137Ser (c.409C>T) in the general population?

FH p.Pro137Ser (c.409C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FH p.Pro137Ser (c.409C>T)?

AlphaMissense predicts likely pathogenic (score 0.9478) — an in-silico prediction, not a clinical call.

FH p.Pro137Ser

c.409C>T · rs2527332837 · VCV1707320

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9478 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9478	likely pathogenic
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -13.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.43	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 16 kb · p 7.5e-09 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FH
Protein: p.Pro137Ser
Coding: c.409C>T
MANE Select: NM_000143
dbSNP: rs2527332837
Type: single nucleotide variant
Location: chr1:241512113 (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

Similar variants

FH p.Pro137Arg Uncertain significance ★★ ⚠ same residue
FH p.Pro137Leu Uncertain significance ★★ ⚠ same residue
FH p.Pro137= Uncertain significance ★ same residue
FH p.Pro137Ala Uncertain significance ★ ⚠ same residue
FH c.1108+1G>A Pathogenic ★★ same type
FH c.1108+1G>T Pathogenic/Likely pathogenic ★★ same type
FH c.1236+1G>A Pathogenic/Likely pathogenic ★★ same type
FH c.1236+1G>C Pathogenic ★★ same type

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-pro137ser (accessed [today's date]).

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