Is AACS p.Arg195Gln (c.584G>A) pathogenic?

AACS p.Arg195Gln (c.584G>A) is classified Uncertain significance in AACS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely pathogenic (0.9369); Ultra-rare (popmax 0.0958%, eas).

How common is AACS p.Arg195Gln (c.584G>A) in the general population?

AACS p.Arg195Gln (c.584G>A) is ultra-rare (popmax 0.0958%, eas) (gnomAD).

What do computational predictors say about AACS p.Arg195Gln (c.584G>A)?

AlphaMissense predicts likely pathogenic (score 0.9369) — an in-silico prediction, not a clinical call.

AACS p.Arg195Gln

c.584G>A · VCV3915537

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9369 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0958%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9369	likely pathogenic · top 10% in AACS
REVEL	0.602	indeterminate
SaProt	LLR -11.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 77 kb · p 0.59 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0958% East Asian · 43/44,874 alleles

Filtering AF 0.0731% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.065%

Overall 0.00477% 77/1,613,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0958%	1,044
African / African-American	0.012%	8,332
South Asian	0.00769%	13,005
Admixed American	0.00333%	30,007
European (non-Finnish)	0.00136%	73,743

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: AACS
Protein: p.Arg195Gln
Coding: c.584G>A
MANE Select: NM_023928
Type: single nucleotide variant
Location: chr12:125102692 (GRCh38)
Gene constraint: LOEUF 0.967 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.09

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

Similar variants

AACS c.1881+8C>G Benign ★★ same type
AACS p.Arg107= Benign ★★ same type
AACS p.Glu564Gln Benign ★★ same type
AACS p.Ile430= Benign ★★ same type
AACS p.Phe276= Benign ★★ same type
AACS p.Ala169Thr Uncertain significance ★ ⚠ same type
AACS p.Ala271Pro Uncertain significance ★ ⚠ same type
AACS p.Ala349Val Uncertain significance ★ ⚠ same type

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/aacs-p-arg195gln (accessed [today's date]).

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