Is AACS p.Cys425Arg (c.1273T>C) pathogenic?

AACS p.Cys425Arg (c.1273T>C) is classified Uncertain significance in AACS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.1858); Ultra-rare (popmax 0.0327%, nfe).

How common is AACS p.Cys425Arg (c.1273T>C) in the general population?

AACS p.Cys425Arg (c.1273T>C) is ultra-rare (popmax 0.0327%, nfe) (gnomAD).

What do computational predictors say about AACS p.Cys425Arg (c.1273T>C)?

AlphaMissense predicts likely benign (score 0.1858) — an in-silico prediction, not a clinical call.

AACS p.Cys425Arg

c.1273T>C · VCV4136413

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1858 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0327%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1858	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -7.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	donor gain, 36 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.72	GERP -1.9
Regional constraint	o/e 0.98	unconstrained · MANE · 77 kb · p 0.59 · regional, not allelic
Overall
CADD	13.2	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 0.0327% European (non-Finnish) · 386/1,180,034 alleles

Filtering AF 0.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0289%

Overall 0.0252% 406/1,614,008 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0327%	3,057
Remaining individualsnot grpmax-eligible	0.0208%	4,807
Finnishnot grpmax-eligible	0.00625%	16,006
African / African-American	0.00401%	24,964

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.Cys425Arg
Coding: c.1273T>C
MANE Select: NM_023928
Type: single nucleotide variant
Location: chr12:125124988 (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-cys425arg (accessed [today's date]).

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