Is AFG2A p.Asp277Val (c.830A>T) pathogenic?

AFG2A p.Asp277Val (c.830A>T) is classified Conflicting classifications of pathogenicity in AFG2A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.0782); Ultra-rare (popmax 0.0755%, nfe); Associated with Inborn genetic diseases.

How common is AFG2A p.Asp277Val (c.830A>T) in the general population?

AFG2A p.Asp277Val (c.830A>T) is ultra-rare (popmax 0.0755%, nfe) (gnomAD).

What do computational predictors say about AFG2A p.Asp277Val (c.830A>T)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

AFG2A p.Asp277Val

Q: What condition is associated with AFG2A p.Asp277Val (c.830A>T)?

AFG2A p.Asp277Val (c.830A>T) is associated with Inborn genetic diseases, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.830A>T · rs150370442 · VCV542383

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0755%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -6.38	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	GERP -3, phastCons 0.001
Regional constraint	o/e 0.99	unconstrained · MANE · 105 kb · p 0.81 · regional, not allelic
Overall
CADD	13.81	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0755% European (non-Finnish) · 891/1,180,052 alleles

Filtering AF 0.0713% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0697%

Overall 0.0582% 939/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0755%	1,324
Remaining individualsnot grpmax-eligible	0.0432%	2,314
Admixed American	0.0167%	6,002
African / African-American	0.0133%	7,493
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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.Asp277Val
Coding: c.830A>T
MANE Select: NM_145207
dbSNP: rs150370442
Type: single nucleotide variant
Location: chr4:122934421 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 277: a UniProt-annotated variant site (in nedhsb)

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

Also linked: microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome

Similar variants

AFG2A p.Asp277Ala Uncertain significance ★ ⚠ same residue
AFG2A c.1714+1G>A Pathogenic ★★ same condition
AFG2A c.446+1G>A Likely pathogenic ★★ same condition
AFG2A p.Ala844Val Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg445Ter Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg510Ter Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg514Ter Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg538Ter Pathogenic/Likely pathogenic ★★ 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-asp277val (accessed [today's date]).

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