Is AFG2B p.Ser333Ile (c.998G>T) pathogenic?

AFG2B p.Ser333Ile (c.998G>T) is classified Uncertain significance in AFG2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-26). AlphaMissense: likely benign (0.1362); Ultra-rare (popmax 0.0551%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AFG2B p.Ser333Ile (c.998G>T)?

AFG2B p.Ser333Ile (c.998G>T) is associated with Inborn genetic diseases (ClinVar).

How common is AFG2B p.Ser333Ile (c.998G>T) in the general population?

AFG2B p.Ser333Ile (c.998G>T) is ultra-rare (popmax 0.0551%, nfe) (gnomAD).

What do computational predictors say about AFG2B p.Ser333Ile (c.998G>T)?

AlphaMissense predicts likely benign (score 0.1362) — an in-silico prediction, not a clinical call.

AFG2B p.Ser333Ile

c.998G>T · rs78045939 · VCV2347357

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1362 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0551%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1362	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -9.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -1.3, phastCons 0.008
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · regional, not allelic
Overall
CADD	19.62	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 0.0551% European (non-Finnish) · 650/1,178,946 alleles

Filtering AF 0.0516% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0502%

Overall 0.0418% 673/1,609,862 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0551%	1,814
Remaining individualsnot grpmax-eligible	0.0192%	5,199
African / African-American	0.0121%	8,284
Admixed American	0.00168%	59,694
Finnishnot grpmax-eligible	0.0016%	62,680

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: AFG2B
Protein: p.Ser333Ile
Coding: c.998G>T
MANE Select: NM_024063
dbSNP: rs78045939
Type: single nucleotide variant
Location: chr15:45403427 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 2 PDB

Full AFG2B 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

AFG2B p.Arg28Cys Uncertain significance ★★ ⚠ same condition
AFG2B p.Pro558Arg Uncertain significance ★★ ⚠ same condition
AFG2B p.Tyr738Cys Uncertain significance ★★ ⚠ same condition
AFG2B p.Ala130Thr Uncertain significance ★ ⚠ same condition
AFG2B p.Ala130Val Uncertain significance ★ ⚠ same condition
AFG2B p.Ala135Thr Uncertain significance ★ ⚠ same condition
AFG2B p.Ala156Ser Uncertain significance ★ ⚠ same condition
AFG2B p.Ala225Val 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/afg2b-p-ser333ile (accessed [today's date]).

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