Is AAAS p.Ser263Pro (c.787T>C) pathogenic?

AAAS p.Ser263Pro (c.787T>C) is classified Pathogenic/Likely pathogenic in AAAS (ClinVar, Multiple submitters, 14 submitters; last evaluated 2025-07-17). AlphaMissense: likely pathogenic (0.9852); Very rare (popmax 0.00703%, nfe); Associated with AAAS-related disorder.

What condition is associated with AAAS p.Ser263Pro (c.787T>C)?

AAAS p.Ser263Pro (c.787T>C) is associated with AAAS-related disorder, hyperreflexia, triple-A syndrome (ClinVar).

How common is AAAS p.Ser263Pro (c.787T>C) in the general population?

AAAS p.Ser263Pro (c.787T>C) is very rare (popmax 0.00703%, nfe) (gnomAD).

What do computational predictors say about AAAS p.Ser263Pro (c.787T>C)?

AlphaMissense predicts likely pathogenic (score 0.9852) — an in-silico prediction, not a clinical call.

AAAS p.Ser263Pro

c.787T>C · rs121918550 · VCV5045

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.9852 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00703%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AAAS-related disorder

Computational evidence

Protein change
AlphaMissense	0.9852	likely pathogenic ✓ concordant with ClinVar · top 5% in AAAS
REVEL	0.844	moderately pathogenic-leaning
SaProt	LLR -11.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 14 kb · p 0.27 · regional, not allelic
Overall
CADD	29.2	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 0.00703% European (non-Finnish) · 83/1,179,936 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00533%

Overall 0.00762% 123/1,613,720 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0547%	1,829
European (non-Finnish)grpmax	0.00703%	14,216
Remaining individualsnot grpmax-eligible	0.0064%	15,618
African / African-American	0.00133%	75,056

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser263Pro
Coding: c.787T>C
MANE Select: NM_015665
dbSNP: rs121918550
Type: single nucleotide variant
Location: chr12:53309624 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.45 · 2 PDB
Residue 263: a UniProt-annotated variant site (in aaas)

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

Disease context

AAAS-related disorder

Also linked: hyperreflexia triple-A syndrome

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-ser263pro (accessed [today's date]).

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