Is AFG2A p.Arg31Trp (c.91C>T) pathogenic?

AFG2A p.Arg31Trp (c.91C>T) is classified Uncertain significance in AFG2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.105); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with AFG2A p.Arg31Trp (c.91C>T)?

AFG2A p.Arg31Trp (c.91C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AFG2A p.Arg31Trp (c.91C>T) in the general population?

AFG2A p.Arg31Trp (c.91C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about AFG2A p.Arg31Trp (c.91C>T)?

AlphaMissense predicts likely benign (score 0.105) — an in-silico prediction, not a clinical call.

AFG2A p.Arg31Trp

c.91C>T · VCV4571718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.105	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -8.86	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 -0.6	GERP -3.3
Regional constraint	o/e 0.99	unconstrained · MANE · 105 kb · p 0.81 · regional, not allelic
Overall
CADD	12.78	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 0.00133% African / African-American · 1/75,048 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,882 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,048
European (non-Finnish)	0.000254%	393,348

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: AFG2A
Protein: p.Arg31Trp
Coding: c.91C>T
MANE Select: NM_145207
Type: single nucleotide variant
Location: chr4:122923233 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 31: the 'required for interaction with afg2b and cinp' region

Full AFG2A 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

AFG2A p.Arg31Gln Uncertain significance ★ ⚠ same residue
AFG2A p.Arg31= Likely benign ★ same residue
AFG2A p.Ala128Thr Uncertain significance ★★ ⚠ same condition
AFG2A p.Ala128Val Uncertain significance ★★ ⚠ same condition
AFG2A p.Ala742Ser Uncertain significance ★★ ⚠ same condition
AFG2A p.Ala742Val Uncertain significance ★★ ⚠ same condition
AFG2A p.Arg501Cys Uncertain significance ★★ ⚠ same condition
AFG2A p.Arg879Cys 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/afg2a-p-arg31trp (accessed [today's date]).

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