Is ACE p.Arg1286Ser (c.3856C>A) pathogenic?

ACE p.Arg1286Ser (c.3856C>A) is classified Benign in ACE (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1364); Common (popmax 11.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with renal tubular dysgenesis.

What condition is associated with ACE p.Arg1286Ser (c.3856C>A)?

ACE p.Arg1286Ser (c.3856C>A) is associated with renal tubular dysgenesis (ClinVar).

What do computational predictors say about ACE p.Arg1286Ser (c.3856C>A)?

AlphaMissense predicts likely benign (score 0.1364) — an in-silico prediction, not a clinical call.

ACE p.Arg1286Ser

Q: How common is ACE p.Arg1286Ser (c.3856C>A) in the general population?

ACE p.Arg1286Ser (c.3856C>A) is common (popmax 11.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3856C>A · rs4364 · VCV256808

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1364 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 11.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal tubular dysgenesis

Computational evidence

Protein change
AlphaMissense	0.1364	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -7.11	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 3.7	GERP 1.5, phastCons 0.15
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	13.57	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 11.8% African / African-American · 8,667/73,348 alleles

Filtering AF 11.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.5%

Overall 0.634% 9,837/1,550,850 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	11.8%	8
Admixed American	0.86%	116
Remaining individualsnot grpmax-eligible	0.824%	121
Middle Eastern	0.463%	216
South Asian	0.0391%	2,555
European (non-Finnish)	0.0155%	6,453

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: ACE
Protein: p.Arg1286Ser
Coding: c.3856C>A
MANE Select: NM_000789
dbSNP: rs4364
Type: single nucleotide variant
Location: chr17:63497301 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 1286: a UniProt-annotated variant site (in)

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

Disease context

renal tubular dysgenesis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACE p.Arg1286Cys Uncertain significance ★ ⚠ same residue
ACE p.Arg1286His Conflicting classifications of pathogenicity ★ ⚠ same residue
ACE c.1709+5G>C Pathogenic/Likely pathogenic ★★ same condition
ACE c.3503+1G>C Likely pathogenic ★★ same condition
ACE p.Arg496Ter Pathogenic/Likely pathogenic ★★ same condition
ACE p.Arg508Ter Pathogenic ★★ same condition
ACE p.Arg791Ter Pathogenic ★★ same condition
ACE p.Tyr266Ter Pathogenic/Likely 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/ace-p-arg1286ser (accessed [today's date]).

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