Is ERLIN1 p.Ala254= (c.762C>A) pathogenic?

ERLIN1 p.Ala254= (c.762C>A) is classified Conflicting classifications of pathogenicity in ERLIN1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-23). Rare (popmax 0.215%, mid); Associated with hereditary spastic paraplegia 62.

What condition is associated with ERLIN1 p.Ala254= (c.762C>A)?

ERLIN1 p.Ala254= (c.762C>A) is associated with hereditary spastic paraplegia 62, hereditary spastic paraplegia (ClinVar).

How common is ERLIN1 p.Ala254= (c.762C>A) in the general population?

ERLIN1 p.Ala254= (c.762C>A) is rare (popmax 0.215%, mid) (gnomAD).

How is Autosomal recessive spastic paraplegia type 62 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ERLIN1 p.Ala254=

c.762C>A · rs143495333 · VCV1344326

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.215%, mid)

Conditions

hereditary spastic paraplegia 62

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 0.76	GERP -2, phastCons 1
Overall
CADD	6.679	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.215% Middle Eastern · 13/6,060 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.0155% 250/1,613,686 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.215%	466
Remaining individualsnot grpmax-eligible	0.0304%	3,288
Admixed American	0.0283%	3,531
European (non-Finnish)	0.0169%	5,928
African / African-American	0.00133%	74,980
South Asian	0.0011%	91,060

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: ERLIN1
Protein: p.Ala254=
Coding: c.762C>A
MANE Select: NM_006459
dbSNP: rs143495333
Type: single nucleotide variant
Location: chr10:100154923 (GRCh38)
Gene constraint: LOEUF 1.049 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 85.49 · 4 PDB

Full ERLIN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 62 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia

For Autosomal recessive spastic paraplegia type 62 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

ERLIN1 p.Ala254Ser Uncertain significance ★★ ⚠ same residue
ERLIN1 p.Ala23Thr Uncertain significance ★★ ⚠ same condition
ERLIN1 p.Ala258Val Uncertain significance ★★ ⚠ same condition
ERLIN1 p.Ala292Ser Uncertain significance ★★ ⚠ same condition
ERLIN1 p.Arg230Trp Uncertain significance ★★ ⚠ same condition
ERLIN1 p.Arg243His Uncertain significance ★★ ⚠ same condition
ERLIN1 p.His26Asp Uncertain significance ★★ ⚠ same condition
ERLIN1 p.Ile223Thr Uncertain significance ★★ ⚠ 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/erlin1-p-ala254 (accessed [today's date]).

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