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

ANG p.Arg75Ser (c.223C>A) is classified Uncertain significance in ANG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely benign (0.0945); Very rare (popmax 8.47e-05%, nfe).

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

ANG p.Arg75Ser (c.223C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

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

AlphaMissense predicts likely benign (score 0.0945) — an in-silico prediction, not a clinical call.

ANG p.Arg75Ser

c.223C>A · VCV4706257

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0945 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0945	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -5.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.87	GERP -2.8
Regional constraint	o/e 0.95	unconstrained · MANE · 440 bp · p 0.49 · regional, not allelic
Overall
CADD	0.626	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 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 6.84e-05% 1/1,461,894 alleles · very rare

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: ANG
Protein: p.Arg75Ser
Coding: c.223C>A
MANE Select: NM_001097577
Type: single nucleotide variant
Location: chr14:20693787 (GRCh38)
Gene constraint: LOEUF 1.697 · pLI 0.42 (gnomAD)
Structure: AlphaFold pLDDT 90.50 · 56 PDB
Residue 75: a disulfide bond; an α-helix

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

Similar variants

ANG p.Arg75His Uncertain significance ★★ ⚠ same residue
ANG p.Arg75Gly Likely benign ★ same residue
ANG p.Gly123Ala Uncertain significance ★★ ⚠ same type
ANG p.Gly15Ser Uncertain significance ★★ ⚠ same type
ANG p.Lys78Glu Uncertain significance ★★ ⚠ same type
ANG p.Pro21Leu Uncertain significance ★★ ⚠ same type
ANG p.Pro21Ser Uncertain significance ★★ ⚠ same type
ANG c.-18-222G>C Benign ★★ 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/ang-p-arg75ser (accessed [today's date]).

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