Is AAAS p.Arg312Ter (c.934C>T) pathogenic?

AAAS p.Arg312Ter (c.934C>T) is classified Pathogenic/Likely pathogenic in AAAS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-11-06). Very rare (popmax 0.00267%, afr); Associated with triple-A syndrome.

What condition is associated with AAAS p.Arg312Ter (c.934C>T)?

AAAS p.Arg312Ter (c.934C>T) is associated with triple-A syndrome (ClinVar).

How common is AAAS p.Arg312Ter (c.934C>T) in the general population?

AAAS p.Arg312Ter (c.934C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Triple A syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

AAAS p.Arg312Ter

c.934C>T · rs121918547 · VCV5039

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

triple-A syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 16
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,038 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000372% 6/1,614,144 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,519
European (non-Finnish)	0.000339%	295,006

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: AAAS
Protein: p.Arg312Ter
Coding: c.934C>T
MANE Select: NM_015665
dbSNP: rs121918547
Type: single nucleotide variant
Location: chr12:53309158 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.45 · 2 PDB
Residue 312: a UniProt-annotated variant site (in aaas); a UniProt-annotated variant site (in aaas; uncertain significance)

Full AAAS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

triple-A syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Triple A syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

AAAS c.1331+1G>A Pathogenic ★★ same condition
AAAS c.1331+1G>C Pathogenic/Likely pathogenic ★★ same condition
AAAS c.446+1G>A Pathogenic ★★ same condition
AAAS c.446+1G>T Pathogenic/Likely pathogenic ★★ same condition
AAAS c.810+1G>A Pathogenic/Likely pathogenic ★★ same condition
AAAS c.936-1G>C Pathogenic/Likely pathogenic ★★ same condition
AAAS p.Ala167Glu Pathogenic/Likely pathogenic ★★ same condition
AAAS p.Ala167Val 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/aaas-p-arg312ter (accessed [today's date]).

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