Is PGC p.Ser333Phe (c.998C>T) pathogenic?

PGC p.Ser333Phe (c.998C>T) is classified Uncertain significance in PGC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-15). AlphaMissense: likely benign (0.2259); Very rare (popmax 8.57e-05%, nfe).

How common is PGC p.Ser333Phe (c.998C>T) in the general population?

PGC p.Ser333Phe (c.998C>T) is very rare (popmax 8.57e-05%, nfe) (gnomAD).

What do computational predictors say about PGC p.Ser333Phe (c.998C>T)?

AlphaMissense predicts likely benign (score 0.2259) — an in-silico prediction, not a clinical call.

PGC p.Ser333Phe

c.998C>T · VCV4135279

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2259 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.57e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2259	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -12.12	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 3.8, phastCons 0.9
Regional constraint	o/e 0.97	unconstrained · MANE · 10 kb · p 0.46 · regional, not allelic
Overall
CADD	22.9	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 8.57e-05% European (non-Finnish) · 1/1,167,312 alleles

Overall 6.25e-05% 1/1,600,202 alleles · very rare exomes 1/1,447,914 · genomes 0/152,288 · 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: PGC
Protein: p.Ser333Phe
Coding: c.998C>T
MANE Select: NM_002630
Type: single nucleotide variant
Location: chr6:41737746 (GRCh38)
Gene constraint: LOEUF 0.991 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 2 PDB
Residue 333: the peptidase a1 domain; an α-helix

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

Similar variants

PGC p.Ala174Val Uncertain significance ★ ⚠ same type
PGC p.Ala183Thr Uncertain significance ★ ⚠ same type
PGC p.Ala186Val Uncertain significance ★ ⚠ same type
PGC p.Ala224Pro Uncertain significance ★ ⚠ same type
PGC p.Ala242Val Uncertain significance ★ ⚠ same type
PGC p.Ala388Thr Uncertain significance ★ ⚠ same type
PGC p.Ala67Gly Uncertain significance ★ ⚠ same type
PGC p.Ala67Val 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/pgc-p-ser333phe (accessed [today's date]).

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