Is SERPING1 p.Arg499Ser (c.1497G>C) pathogenic?

SERPING1 p.Arg499Ser (c.1497G>C) is classified Uncertain significance in SERPING1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-31). AlphaMissense: likely benign (0.2266); Very rare (popmax 8.47e-05%, nfe).

How common is SERPING1 p.Arg499Ser (c.1497G>C) in the general population?

SERPING1 p.Arg499Ser (c.1497G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about SERPING1 p.Arg499Ser (c.1497G>C)?

AlphaMissense predicts likely benign (score 0.2266) — an in-silico prediction, not a clinical call.

SERPING1 p.Arg499Ser

c.1497G>C · rs1383385545 · VCV2119871

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2266 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2266	likely benign
REVEL	0.259	benign-leaning
SaProt	LLR -3.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.28	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.31	GERP -0.076
Regional constraint	o/e 0.83	unconstrained · MANE · 16 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	15.17	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 6.2e-05% 1/1,613,650 alleles · very rare exomes 1/1,461,364 · genomes 0/152,286 · 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: SERPING1
Protein: p.Arg499Ser
Coding: c.1497G>C
MANE Select: NM_000062
dbSNP: rs1383385545
Type: single nucleotide variant
Location: chr11:57614575 (GRCh38)
Gene constraint: LOEUF 0.278 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.63 · 5 PDB

Full SERPING1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SERPING1 p.Arg499= Likely benign ★ same residue
SERPING1 c.1030-1G>T Pathogenic ★★ same type
SERPING1 c.51+1G>T Pathogenic ★★ same type
SERPING1 c.51+3A>C Pathogenic/Likely pathogenic ★★ same type
SERPING1 c.51+3A>G Pathogenic ★★ same type
SERPING1 c.52-1G>A Pathogenic ★★ same type
SERPING1 c.550+1G>A Pathogenic ★★ same type
SERPING1 c.551-1G>C 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/serping1-p-arg499ser (accessed [today's date]).

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