Is ACE p.Ser683= (c.2049C>T) pathogenic?

ACE p.Ser683= (c.2049C>T) is classified Uncertain significance in ACE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-09). Very rare (popmax 0.00644%, nfe); Associated with renal tubular dysgenesis of genetic origin.

What condition is associated with ACE p.Ser683= (c.2049C>T)?

ACE p.Ser683= (c.2049C>T) is associated with renal tubular dysgenesis of genetic origin, microvascular complications of diabetes, susceptibility to, 3, hemorrhage, intracerebral, susceptibility to (ClinVar).

How common is ACE p.Ser683= (c.2049C>T) in the general population?

ACE p.Ser683= (c.2049C>T) is very rare (popmax 0.00644%, nfe) (gnomAD).

ACE p.Ser683=

c.2049C>T · VCV3582514

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00644%, nfe)

Conditions

renal tubular dysgenesis of genetic origin

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.98	donor gain · deltas
Pangolin	Δ0.84	gain · loss 0.63 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.3	GERP 0.41, phastCons 1
Overall
CADD	19.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00644% European (non-Finnish) · 76/1,180,014 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00477% 77/1,613,960 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00644%	15,527
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Ser683=
Coding: c.2049C>T
MANE Select: NM_000789
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

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

Also linked: microvascular complications of diabetes, susceptibility to, 3 hemorrhage, intracerebral, susceptibility to

Similar variants

ACE p.Ser683Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
ACE c.1342+1G>T 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.Arg508Ter Pathogenic ★★ same condition
ACE p.Arg791Ter Pathogenic ★★ same condition
ACE p.Gln396Ter 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-ser683 (accessed [today's date]).

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