Is ALG10B p.Pro141Ser (c.421C>T) pathogenic?

ALG10B p.Pro141Ser (c.421C>T) is classified Uncertain significance in ALG10B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely pathogenic (0.9587); Very rare (popmax 0.00167%, amr).

How common is ALG10B p.Pro141Ser (c.421C>T) in the general population?

ALG10B p.Pro141Ser (c.421C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ALG10B p.Pro141Ser (c.421C>T)?

AlphaMissense predicts likely pathogenic (score 0.9587) — an in-silico prediction, not a clinical call.

ALG10B p.Pro141Ser

c.421C>T · VCV4639944

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9587 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9587	likely pathogenic · top 5% in ALG10B
REVEL	0.77	pathogenic-leaning
SaProt	LLR -10.51	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 7.4	phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 4,316 bp · p 0.37 · regional, not allelic
Overall
CADD	24.4	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

Grpmax group 0.00167% Admixed American · 1/60,004 alleles

Overall 6.2e-05% 1/1,613,976 alleles · very rare exomes 1/1,461,756 · genomes 0/152,220 · joint denominator

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: ALG10B
Protein: p.Pro141Ser
Coding: c.421C>T
MANE Select: NM_001013620
Type: single nucleotide variant
Location: chr12:38320212 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.14

Full ALG10B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALG10B p.Gln469= Benign ★★ same type
ALG10B p.Ala125Asp Uncertain significance ★ ⚠ same type
ALG10B p.Ala163Val Uncertain significance ★ ⚠ same type
ALG10B p.Ala176Gly Uncertain significance ★ ⚠ same type
ALG10B p.Ala2Ser Uncertain significance ★ ⚠ same type
ALG10B p.Ala2Val Uncertain significance ★ ⚠ same type
ALG10B p.Ala385Val Uncertain significance ★ ⚠ same type
ALG10B p.Arg186Trp Uncertain significance ★ ⚠ 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/alg10b-p-pro141ser (accessed [today's date]).

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