Is PRAME p.Ser421= (c.1263T>C) pathogenic?

PRAME p.Ser421= (c.1263T>C) is classified Benign in PRAME (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-29). Common (popmax 5.63%, afr) — too common for a highly-penetrant pathogenic allele.

PRAME p.Ser421=

Q: How common is PRAME p.Ser421= (c.1263T>C) in the general population?

PRAME p.Ser421= (c.1263T>C) is common (popmax 5.63%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1263T>C · rs2229696 · VCV777670

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 5.63%, afr) — too common for a highly-penetrant pathogenic allele

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -15	GERP -3.4
Overall
CADD	0.418	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.63% African / African-American · 4,218/74,970 alleles

Filtering AF 5.48% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.43%

Overall 0.311% 5,026/1,613,652 alleles · common exomes 2,588/1,461,626 · genomes 2,438/152,026 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.63%	18
Admixed American	0.455%	220
Remaining individualsnot grpmax-eligible	0.357%	280
Middle Eastern	0.198%	505
Ashkenazi Jewishnot grpmax-eligible	0.128%	779
European (non-Finnish)	0.0221%	4,521
South Asian	0.0011%	91,062

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: PRAME
Protein: p.Ser421=
Coding: c.1263T>C
MANE Select: NM_206956
dbSNP: rs2229696
Type: single nucleotide variant
Location: chr22:22548334 (GRCh38)

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

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/prame-p-ser421 (accessed [today's date]).

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