Is AACS p.Arg75Ser (c.223C>A) pathogenic?

AACS p.Arg75Ser (c.223C>A) is classified Uncertain significance in AACS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.1821); Very rare (popmax 0.00667%, amr).

How common is AACS p.Arg75Ser (c.223C>A) in the general population?

AACS p.Arg75Ser (c.223C>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about AACS p.Arg75Ser (c.223C>A)?

AlphaMissense predicts likely benign (score 0.1821) — an in-silico prediction, not a clinical call.

AACS p.Arg75Ser

c.223C>A · VCV4148836

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1821	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -6.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.52	GERP -1.6, phastCons 0.004
Regional constraint	o/e 0.98	unconstrained · MANE · 77 kb · p 0.59 · regional, not allelic
Overall
CADD	8.346	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 0.00667% Admixed American · 4/59,958 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000616% 9/1,461,174 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,989
European (non-Finnish)	0.000424%	235,891

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.Arg75Ser
Coding: c.223C>A
MANE Select: NM_023928
Type: single nucleotide variant
Location: chr12:125073965 (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 p.Arg75His Uncertain significance ★ ⚠ same residue
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

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-arg75ser (accessed [today's date]).

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