Is ALG1 p.Thr261Ser (c.781A>T) pathogenic?

ALG1 p.Thr261Ser (c.781A>T) is classified Uncertain significance in ALG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). AlphaMissense: ambiguous (0.3513); Ultra-rare (popmax 0.0254%, afr); Associated with Inborn genetic diseases.

What condition is associated with ALG1 p.Thr261Ser (c.781A>T)?

ALG1 p.Thr261Ser (c.781A>T) is associated with Inborn genetic diseases (ClinVar).

How common is ALG1 p.Thr261Ser (c.781A>T) in the general population?

ALG1 p.Thr261Ser (c.781A>T) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

What do computational predictors say about ALG1 p.Thr261Ser (c.781A>T)?

AlphaMissense predicts ambiguous (score 0.3513) — an in-silico prediction, not a clinical call.

ALG1 p.Thr261Ser

c.781A>T · rs377260474 · VCV2474248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3513 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3513	ambiguous
REVEL	0.458	indeterminate
SaProt	LLR -8.52	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.6, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	20.9	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 0.0254% African / African-American · 19/74,890 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.0013% 21/1,612,680 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,942
Admixed American	0.00333%	30,001

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: ALG1
Protein: p.Thr261Ser
Coding: c.781A>T
MANE Select: NM_019109
dbSNP: rs377260474
Type: single nucleotide variant
Location: chr16:5078797 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.24
Residue 261: the 'disordered' region

Full ALG1 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

ALG1 p.Thr261Met Uncertain significance ★★ ⚠ same residue
ALG1 p.Thr261Ala Uncertain significance ★ ⚠ same residue
ALG1 p.Thr261= Likely benign ★ same residue
ALG1 p.Ala360Val Pathogenic/Likely pathogenic ★★ same condition
ALG1 p.Gln342Pro Pathogenic/Likely pathogenic ★★ ⚠ same condition
ALG1 p.Ala278Thr Uncertain significance ★★ ⚠ same condition
ALG1 p.Arg257Gln Uncertain significance ★★ ⚠ same condition
ALG1 p.Asn311Lys 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/alg1-p-thr261ser (accessed [today's date]).

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