Is FH p.Pro309Ser (c.925C>T) pathogenic?

FH p.Pro309Ser (c.925C>T) is classified Conflicting classifications of pathogenicity in FH (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.1253); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Pro309Ser (c.925C>T)?

FH p.Pro309Ser (c.925C>T) is associated with hereditary neoplastic syndrome, fumaric aciduria (ClinVar).

How common is FH p.Pro309Ser (c.925C>T) in the general population?

FH p.Pro309Ser (c.925C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about FH p.Pro309Ser (c.925C>T)?

AlphaMissense predicts likely benign (score 0.1253) — an in-silico prediction, not a clinical call.

FH p.Pro309Ser

c.925C>T · rs368849989 · VCV405930

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1253 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1253	likely benign
REVEL	0.827	moderately pathogenic-leaning
SaProt	LLR -9.81	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 16 kb · p 7.5e-09 · regional, not allelic
Overall
CADD	24.9	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 0.00223% East Asian · 1/44,882 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.0013% 21/1,614,096 alleles · very rare exomes 18/1,461,814 · genomes 3/152,282 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.016%	6,250
East Asiangrpmax	0.00223%	44,882
Admixed American	0.00167%	60,020
South Asian	0.0011%	91,074
European (non-Finnish)	0.000678%	147,500

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro309Ser
Coding: c.925C>T
MANE Select: NM_000143
dbSNP: rs368849989
Type: single nucleotide variant
Location: chr1:241504225 (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

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

Also linked: fumaric aciduria

Similar variants

FH p.Pro309= Benign ★★ same residue
FH p.Pro309Arg Uncertain significance ★ ⚠ same residue
FH p.Pro309Leu Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro309ser (accessed [today's date]).

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