Is FH p.Pro177Arg (c.530C>G) pathogenic?

FH p.Pro177Arg (c.530C>G) is classified Likely pathogenic in FH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-08). AlphaMissense: likely pathogenic (0.9927); Absent from gnomAD v4.1.

How common is FH p.Pro177Arg (c.530C>G) in the general population?

FH p.Pro177Arg (c.530C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FH p.Pro177Arg (c.530C>G)?

AlphaMissense predicts likely pathogenic (score 0.9927) — an in-silico prediction, not a clinical call.

FH p.Pro177Arg

c.530C>G · rs2147921795 · VCV1485377

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9927 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9927	likely pathogenic ✓ concordant with ClinVar
REVEL	0.95	strongly pathogenic-leaning
SaProt	LLR -18.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	31.0	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

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.Pro177Arg
Coding: c.530C>G
MANE Select: NM_000143
dbSNP: rs2147921795
Type: single nucleotide variant
Location: chr1:241511992 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 177: a binding site; an α-helix

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

Similar variants

FH p.Pro177= Benign ★ 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
FH c.1236+2T>G Pathogenic ★★ same type
FH c.1237-1G>T Likely pathogenic ★★ same type
FH c.1390+1G>T Pathogenic/Likely 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-pro177arg (accessed [today's date]).

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