Is ACE p.Ser346= (c.1038G>C) pathogenic?

ACE p.Ser346= (c.1038G>C) is classified Benign/Likely benign in ACE (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-23). Low-frequency (popmax 4.17%, mid); Associated with renal tubular dysgenesis.

How common is ACE p.Ser346= (c.1038G>C) in the general population?

ACE p.Ser346= (c.1038G>C) is low-frequency (popmax 4.17%, mid) (gnomAD).

ACE p.Ser346=

Q: What condition is associated with ACE p.Ser346= (c.1038G>C)?

ACE p.Ser346= (c.1038G>C) is associated with renal tubular dysgenesis, renal tubular dysgenesis of genetic origin, microvascular complications of diabetes, susceptibility to, 3 (ClinVar).

c.1038G>C · rs34680431 · VCV778721

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.17%, mid)

Conditions

renal tubular dysgenesis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.1	GERP -3.7
Overall
CADD	1.824	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.17% Middle Eastern · 253/6,060 alleles

Filtering AF 3.75% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.59%

Overall 0.405% 6,540/1,614,060 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	4.17%	24
Ashkenazi Jewishnot grpmax-eligible	0.898%	111
Remaining individualsnot grpmax-eligible	0.792%	126
Admixed American	0.701%	143
African / African-American	0.648%	154
European (non-Finnish)	0.365%	274
South Asian	0.28%	357
Finnishnot grpmax-eligible	0.086%	1,163
East Asian	0.00223%	44,858

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.Ser346=
Coding: c.1038G>C
MANE Select: NM_000789
dbSNP: rs34680431
Type: single nucleotide variant
Location: chr17:63481658 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 346: the peptidase m2 1 domain

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

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

Similar variants

ACE p.Ser346Leu 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-ser346 (accessed [today's date]).

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