Is ALS2 p.Tyr1649Ser (c.4946A>C) pathogenic?

ALS2 p.Tyr1649Ser (c.4946A>C) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-22). AlphaMissense: likely pathogenic (0.6614); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ALS2 p.Tyr1649Ser (c.4946A>C)?

ALS2 p.Tyr1649Ser (c.4946A>C) is associated with Inborn genetic diseases (ClinVar).

How common is ALS2 p.Tyr1649Ser (c.4946A>C) in the general population?

ALS2 p.Tyr1649Ser (c.4946A>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ALS2 p.Tyr1649Ser (c.4946A>C)?

AlphaMissense predicts likely pathogenic (score 0.6614) — an in-silico prediction, not a clinical call.

ALS2 p.Tyr1649Ser

c.4946A>C · rs1559025522 · VCV2256441

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6614 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6614	likely pathogenic
REVEL	0.155	moderately benign-leaning
SaProt	LLR -5.60	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	23.0	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 8.48e-05% European (non-Finnish) · 1/1,179,888 alleles

Overall 0.000658% 1/152,058 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: ALS2
Protein: p.Tyr1649Ser
Coding: c.4946A>C
MANE Select: NM_020919
dbSNP: rs1559025522
Type: single nucleotide variant
Location: chr2:201701879 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 1649: the vps9 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Ala333Ser Uncertain significance ★★ ⚠ same condition
ALS2 p.Ala377Thr Uncertain significance ★★ ⚠ same condition
ALS2 p.Ala402Thr Uncertain significance ★★ ⚠ same condition
ALS2 p.Arg1329Trp Uncertain significance ★★ ⚠ same condition
ALS2 p.Arg1330His Uncertain significance ★★ ⚠ same condition
ALS2 p.Arg1405Cys Uncertain significance ★★ ⚠ same condition
ALS2 p.Arg1461Gln 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/als2-p-tyr1649ser (accessed [today's date]).

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