Is ALS2 p.Cys208Trp (c.624T>G) pathogenic?

ALS2 p.Cys208Trp (c.624T>G) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-29). AlphaMissense: likely pathogenic (0.994); Absent from gnomAD v4.1.

How common is ALS2 p.Cys208Trp (c.624T>G) in the general population?

ALS2 p.Cys208Trp (c.624T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALS2 p.Cys208Trp (c.624T>G)?

AlphaMissense predicts likely pathogenic (score 0.994) — an in-silico prediction, not a clinical call.

ALS2 p.Cys208Trp

c.624T>G · rs1057522810 · VCV387520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.994 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.994	likely pathogenic · top 5% in ALS2
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -17.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.072	GERP 1.7, phastCons 0.061
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0064 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ALS2
Protein: p.Cys208Trp
Coding: c.624T>G
MANE Select: NM_020919
dbSNP: rs1057522810
Type: single nucleotide variant
Location: chr2:201761370 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69

Full ALS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALS2 c.1640+1G>A Pathogenic/Likely pathogenic ★★ same type
ALS2 c.2580+2T>C Pathogenic ★★ same type
ALS2 c.3703-2A>G Pathogenic/Likely pathogenic ★★ same type
ALS2 c.4626+1G>A Pathogenic/Likely pathogenic ★★ same type
ALS2 p.Ala573Glu Likely pathogenic ★★ same type
ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same type
ALS2 p.Arg1421Ter Pathogenic/Likely pathogenic ★★ same type
ALS2 p.Arg1461Ter Pathogenic ★★ 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/als2-p-cys208trp (accessed [today's date]).

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