Is ERLIN1 p.Ala254Ser (c.760G>T) pathogenic?

ERLIN1 p.Ala254Ser (c.760G>T) is classified Uncertain significance in ERLIN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-02). AlphaMissense: likely benign (0.1232); Ultra-rare (popmax 0.0567%, amr); Associated with hereditary spastic paraplegia 62.

What condition is associated with ERLIN1 p.Ala254Ser (c.760G>T)?

ERLIN1 p.Ala254Ser (c.760G>T) is associated with hereditary spastic paraplegia 62 (ClinVar).

How common is ERLIN1 p.Ala254Ser (c.760G>T) in the general population?

ERLIN1 p.Ala254Ser (c.760G>T) is ultra-rare (popmax 0.0567%, amr) (gnomAD).

How is Autosomal recessive spastic paraplegia type 62 inherited?

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

What do computational predictors say about ERLIN1 p.Ala254Ser (c.760G>T)?

AlphaMissense predicts likely benign (score 0.1232) — an in-silico prediction, not a clinical call.

ERLIN1 p.Ala254Ser

c.760G>T · rs752175424 · VCV2051439

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1232 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0567%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 62

Computational evidence

Protein change
AlphaMissense	0.1232	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -7.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.9, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 31 kb · p 3.9e-13 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0567% Admixed American · 34/59,998 alleles

Filtering AF 0.0416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.00694% 112/1,613,614 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0567%	1,765
Remaining individualsnot grpmax-eligible	0.0144%	6,939
European (non-Finnish)	0.00585%	17,097

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.Ala254Ser
Coding: c.760G>T
MANE Select: NM_006459
dbSNP: rs752175424
Type: single nucleotide variant
Location: chr10:100154925 (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

For Autosomal recessive spastic paraplegia type 62 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

ERLIN1 p.Ala254= Conflicting classifications of pathogenicity ★ 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-ala254ser (accessed [today's date]).

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