Is PCSK7 p.Pro424Arg (c.1271C>G) pathogenic?

PCSK7 p.Pro424Arg (c.1271C>G) is classified Uncertain significance in PCSK7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-04). AlphaMissense: likely benign (0.1484); Very rare (popmax 0.00305%, nfe).

How common is PCSK7 p.Pro424Arg (c.1271C>G) in the general population?

PCSK7 p.Pro424Arg (c.1271C>G) is very rare (popmax 0.00305%, nfe) (gnomAD).

What do computational predictors say about PCSK7 p.Pro424Arg (c.1271C>G)?

AlphaMissense predicts likely benign (score 0.1484) — an in-silico prediction, not a clinical call.

PCSK7 p.Pro424Arg

c.1271C>G · VCV3305256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1484 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1484	likely benign
REVEL	0.824	moderately pathogenic-leaning
SaProt	LLR -10.00	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 11 kb · p 1e-05 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.00305% European (non-Finnish) · 36/1,179,464 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00223% 36/1,612,516 alleles · very rare exomes 36/1,460,150 · genomes 0/152,366 · 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: PCSK7
Protein: p.Pro424Arg
Coding: c.1271C>G
MANE Select: NM_004716
Type: single nucleotide variant
Location: chr11:117219643 (GRCh38)
Gene constraint: LOEUF 0.881 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.92
Residue 424: the peptidase s8 domain

Full PCSK7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PCSK7 p.Pro424Ser Uncertain significance ★ ⚠ same residue
PCSK7 p.Arg560Gly Uncertain significance ★★ ⚠ same type
PCSK7 p.Lys545Thr Uncertain significance ★★ ⚠ same type
PCSK7 c.1786+7C>T Benign ★★ same type
PCSK7 p.Leu590= Likely benign ★★ same type
PCSK7 p.Pro777Leu Benign ★★ same type
PCSK7 c.1691+1G>A Uncertain significance ★ same type
PCSK7 p.Ala26Thr Uncertain significance ★ ⚠ 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/pcsk7-p-pro424arg (accessed [today's date]).

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