Is ALG10B p.Ser333Phe (c.998C>T) pathogenic?

ALG10B p.Ser333Phe (c.998C>T) is classified Uncertain significance in ALG10B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.2149); Ultra-rare (popmax 0.0802%, sas).

How common is ALG10B p.Ser333Phe (c.998C>T) in the general population?

ALG10B p.Ser333Phe (c.998C>T) is ultra-rare (popmax 0.0802%, sas) (gnomAD).

What do computational predictors say about ALG10B p.Ser333Phe (c.998C>T)?

AlphaMissense predicts likely benign (score 0.2149) — an in-silico prediction, not a clinical call.

ALG10B p.Ser333Phe

c.998C>T · VCV4270173

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2149 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0802%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2149	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -5.33	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 1.3	phastCons 0.72
Regional constraint	o/e 0.96	unconstrained · MANE · 4,316 bp · p 0.37 · regional, not allelic
Overall
CADD	15.15	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 0.0802% South Asian · 73/91,056 alleles

Filtering AF 0.0654% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0599%

Overall 0.00459% 74/1,613,686 alleles · ultra-rare exomes 67/1,461,712 · genomes 7/151,974 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0802%	1,247
European (non-Finnish)	8.48e-05%	1,179,935

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.Ser333Phe
Coding: c.998C>T
MANE Select: NM_001013620
Type: single nucleotide variant
Location: chr12:38320789 (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-ser333phe (accessed [today's date]).

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