Is SERPING1 p.Ser21Phe (c.62C>T) pathogenic?

SERPING1 p.Ser21Phe (c.62C>T) is classified Conflicting classifications of pathogenicity in SERPING1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-16). AlphaMissense: likely benign (0.0811); Very rare (popmax 0.000593%, nfe).

How common is SERPING1 p.Ser21Phe (c.62C>T) in the general population?

SERPING1 p.Ser21Phe (c.62C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about SERPING1 p.Ser21Phe (c.62C>T)?

AlphaMissense predicts likely benign (score 0.0811) — an in-silico prediction, not a clinical call.

SERPING1 p.Ser21Phe

c.62C>T · VCV3704901

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0811	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.61	GERP -3.4
Regional constraint	o/e 0.83	unconstrained · MANE · 16 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	10.45	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 0.000593% European (non-Finnish) · 7/1,180,052 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,614,036 alleles · very rare exomes 5/1,461,894 · genomes 2/152,142 · 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.Ser21Phe
Coding: c.62C>T
MANE Select: NM_000062
Type: single nucleotide variant
Location: chr11:57599889 (GRCh38)
Gene constraint: LOEUF 0.278 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.63 · 5 PDB
Residue 21: the 'disordered' region

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

Similar variants

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
SERPING1 c.551-2A>G 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-ser21phe (accessed [today's date]).

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