Is SEPSECS p.Pro15= (c.45G>A) pathogenic?

SEPSECS p.Pro15= (c.45G>A) is classified Benign/Likely benign in SEPSECS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-20). Rare (popmax 0.33%, eas); Associated with pontocerebellar hypoplasia type 2D.

What condition is associated with SEPSECS p.Pro15= (c.45G>A)?

SEPSECS p.Pro15= (c.45G>A) is associated with pontocerebellar hypoplasia type 2D (ClinVar).

How common is SEPSECS p.Pro15= (c.45G>A) in the general population?

SEPSECS p.Pro15= (c.45G>A) is rare (popmax 0.33%, eas) (gnomAD).

SEPSECS p.Pro15=

c.45G>A · rs77226826 · VCV761884

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.33%, eas)

Conditions

pontocerebellar hypoplasia type 2D

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.2	GERP -2.1, phastCons 0.97
Overall
CADD	13.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.33% East Asian · 135/40,874 alleles

Filtering AF 0.285% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.268%

Overall 0.0116% 179/1,548,806 alleles · rare exomes 146/1,396,620 · genomes 33/152,186 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.33%	303
South Asian	0.0345%	2,898
Remaining individualsnot grpmax-eligible	0.0183%	5,458
Middle Eastern	0.0167%	5,988
European (non-Finnish)	0.000262%	381,977

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: SEPSECS
Protein: p.Pro15=
Coding: c.45G>A
MANE Select: NM_016955
dbSNP: rs77226826
Type: single nucleotide variant
Location: chr4:25160325 (GRCh38)
Gene constraint: LOEUF 1.096 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.63 · 7 PDB
Residue 15: the 'tetramerization' region; an α-helix

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

Disease context

pontocerebellar hypoplasia type 2D — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SEPSECS p.Pro15Ser Uncertain significance ★ ⚠ same residue
SEPSECS c.1027-2A>G Likely pathogenic ★★ same condition
SEPSECS c.389-1G>A Likely pathogenic ★★ same condition
SEPSECS c.547+1G>C Likely pathogenic ★★ same condition
SEPSECS p.Ala239Thr Pathogenic/Likely pathogenic ★★ same condition
SEPSECS p.Arg156Ter Pathogenic/Likely pathogenic ★★ same condition
SEPSECS p.Arg169Ter Pathogenic/Likely pathogenic ★★ same condition
SEPSECS p.Arg271Ter Pathogenic/Likely 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/sepsecs-p-pro15 (accessed [today's date]).

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