Is BORCS8 p.Ser42Pro (c.124T>C) pathogenic?

BORCS8 p.Ser42Pro (c.124T>C) is classified Pathogenic in BORCS8 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2026-09-22). AlphaMissense: likely pathogenic (0.9977); Very rare (popmax 0.00119%, sas); Associated with neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities.

What condition is associated with BORCS8 p.Ser42Pro (c.124T>C)?

BORCS8 p.Ser42Pro (c.124T>C) is associated with neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities (ClinVar).

How common is BORCS8 p.Ser42Pro (c.124T>C) in the general population?

BORCS8 p.Ser42Pro (c.124T>C) is very rare (popmax 0.00119%, sas) (gnomAD).

What do computational predictors say about BORCS8 p.Ser42Pro (c.124T>C)?

AlphaMissense predicts likely pathogenic (score 0.9977) — an in-silico prediction, not a clinical call.

BORCS8 p.Ser42Pro

c.124T>C · VCV3363152

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities

Computational evidence

Protein change
AlphaMissense	0.9977	likely pathogenic ✓ concordant with ClinVar · top 5% in BORCS8
REVEL	0.525	indeterminate
SaProt	LLR -9.54	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 11 kb · p 0.96 · regional, not allelic
Overall
CADD	27.5	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 0.00119% South Asian · 1/83,996 alleles

Overall 7.15e-05% 1/1,398,254 alleles · very rare

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: BORCS8
Protein: p.Ser42Pro
Coding: c.124T>C
MANE Select: NM_001145784
Type: single nucleotide variant
Location: chr19:19186919 (GRCh38)
Gene constraint: LOEUF 1.104 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.74
Residue 42: a UniProt-annotated variant site (in ndoaba; uncertain significance; decreased function in lysosome localization to peripheral cytoplasm; contrary to the wild type, the mutant does not rescue defects in lysosomal distribution in borcs8-deficient cells; reduced interaction with borcs5 and borcs7)

Full BORCS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BORCS8 p.Glu68Ter Likely pathogenic ★ same condition
BORCS8 p.Gln54Pro Uncertain significance ★ ⚠ same condition
BORCS8 p.Ser29Pro Uncertain significance ★ ⚠ same condition
BORCS8 p.Thr66Pro Pathogenic ⚠ same condition
BORCS8 p.Asn26fs Pathogenic same condition
BORCS8 p.Ala25Gly Uncertain significance ★ ⚠ same type
BORCS8 p.Arg40His Uncertain significance ★ ⚠ same type
BORCS8 p.Arg55Cys 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/borcs8-p-ser42pro (accessed [today's date]).

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