Is ELP1 p.Pro421= (c.1263A>G) pathogenic?

ELP1 p.Pro421= (c.1263A>G) is classified Likely benign in ELP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Ultra-rare (popmax 0.0165%, mid); Associated with medulloblastoma.

What condition is associated with ELP1 p.Pro421= (c.1263A>G)?

ELP1 p.Pro421= (c.1263A>G) is associated with medulloblastoma, Riley-Day syndrome (ClinVar).

How common is ELP1 p.Pro421= (c.1263A>G) in the general population?

ELP1 p.Pro421= (c.1263A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Medulloblastoma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

ELP1 p.Pro421=

c.1263A>G · rs371100951 · VCV698168

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

medulloblastoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.9	GERP -3.6
Overall
CADD	5.959	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000496% 8/1,614,066 alleles · ultra-rare exomes 8/1,461,864 · genomes 0/152,202 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0048%	20,833
African / African-American	0.004%	25,002
South Asian	0.0011%	91,076

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: ELP1
Protein: p.Pro421=
Coding: c.1263A>G
MANE Select: NM_003640
dbSNP: rs371100951
Type: single nucleotide variant
Location: chr9:108911107 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 5 PDB

Full ELP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

medulloblastoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Riley-Day syndrome

For Medulloblastoma (Orphanet):

Inheritance: Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ELP1 c.1361-1G>T Pathogenic/Likely pathogenic ★★ same condition
ELP1 c.1361-2A>G Pathogenic/Likely pathogenic ★★ same condition
ELP1 c.1461-1G>A Likely pathogenic ★★ same condition
ELP1 c.1644-1G>T Likely pathogenic ★★ same condition
ELP1 c.1644-2A>C Likely pathogenic ★★ same condition
ELP1 c.1854+1G>A Likely pathogenic ★★ same condition
ELP1 c.2015-2A>G Likely pathogenic ★★ same condition
ELP1 c.2204+6T>C Pathogenic ★★ same condition

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/elp1-p-pro421 (accessed [today's date]).

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