Is AFG2A p.Cys27Phe (c.80G>T) pathogenic?

AFG2A p.Cys27Phe (c.80G>T) is classified Uncertain significance in AFG2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-03). AlphaMissense: likely benign (0.0636); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with AFG2A p.Cys27Phe (c.80G>T)?

AFG2A p.Cys27Phe (c.80G>T) is associated with Inborn genetic diseases (ClinVar).

How common is AFG2A p.Cys27Phe (c.80G>T) in the general population?

AFG2A p.Cys27Phe (c.80G>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about AFG2A p.Cys27Phe (c.80G>T)?

AlphaMissense predicts likely benign (score 0.0636) — an in-silico prediction, not a clinical call.

AFG2A p.Cys27Phe

c.80G>T · rs35430470 · VCV2217509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0636	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -6.46	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 0.48	GERP -1.1
Regional constraint	o/e 0.99	unconstrained · MANE · 105 kb · p 0.81 · regional, not allelic
Overall
CADD	6.409	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 0.005% Admixed American · 3/60,008 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,614,056 alleles · very rare

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.Cys27Phe
Coding: c.80G>T
MANE Select: NM_145207
dbSNP: rs35430470
Type: single nucleotide variant
Location: chr4:122923222 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 27: the 'required for interaction with afg2b and cinp' region; a UniProt-annotated variant site (in)

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.Cys27Ser 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
AFG2A p.Asn300Ser 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-cys27phe (accessed [today's date]).

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