Is ACE p.Ser683Arg (c.2049C>A) pathogenic?

ACE p.Ser683Arg (c.2049C>A) is classified Conflicting classifications of pathogenicity in ACE (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-24). AlphaMissense: ambiguous (0.5517); Ultra-rare (popmax 0.0215%, nfe); Associated with hemorrhage, intracerebral, susceptibility to.

What condition is associated with ACE p.Ser683Arg (c.2049C>A)?

ACE p.Ser683Arg (c.2049C>A) is associated with hemorrhage, intracerebral, susceptibility to, renal tubular dysgenesis of genetic origin, microvascular complications of diabetes, susceptibility to, 3 (ClinVar).

How common is ACE p.Ser683Arg (c.2049C>A) in the general population?

ACE p.Ser683Arg (c.2049C>A) is ultra-rare (popmax 0.0215%, nfe) (gnomAD).

What do computational predictors say about ACE p.Ser683Arg (c.2049C>A)?

AlphaMissense predicts ambiguous (score 0.5517) — an in-silico prediction, not a clinical call.

ACE p.Ser683Arg

c.2049C>A · rs148491967 · VCV974412

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5517 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0215%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hemorrhage, intracerebral, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.5517	ambiguous
REVEL	0.135	moderately benign-leaning
SaProt	LLR -7.32	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.98 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP 0.41, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	17.46	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 0.0215% European (non-Finnish) · 254/1,180,006 alleles

Filtering AF 0.0193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.0165% 267/1,614,078 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0215%	4,646
Remaining individualsnot grpmax-eligible	0.0144%	6,946
Admixed American	0.00333%	30,011
African / African-American	0.00267%	37,511

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.Ser683Arg
Coding: c.2049C>A
MANE Select: NM_000789
dbSNP: rs148491967
Type: single nucleotide variant
Location: chr17:63485363 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 683: an α-helix; the peptidase m2 2 domain

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

Disease context

hemorrhage, intracerebral, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal tubular dysgenesis of genetic origin microvascular complications of diabetes, susceptibility to, 3 renal tubular dysgenesis

Similar variants

ACE p.Ser683= Uncertain significance ★ same residue
ACE c.1342+1G>T Likely pathogenic ★★ same condition
ACE c.1709+5G>C Pathogenic/Likely pathogenic ★★ same condition
ACE c.3503+1G>C Likely pathogenic ★★ same condition
ACE c.945+2T>G Likely pathogenic ★★ same condition
ACE p.Arg265Ter Pathogenic ★★ same condition
ACE p.Arg496Ter Pathogenic/Likely pathogenic ★★ same condition
ACE p.Arg508Ter 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-ser683arg (accessed [today's date]).

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