Is ACE p.Leu254Pro (c.761T>C) pathogenic?

ACE p.Leu254Pro (c.761T>C) is classified Uncertain significance in ACE (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely pathogenic (0.9944); Absent from gnomAD v4.1; Associated with renal tubular dysgenesis.

What condition is associated with ACE p.Leu254Pro (c.761T>C)?

ACE p.Leu254Pro (c.761T>C) is associated with renal tubular dysgenesis (ClinVar).

How common is ACE p.Leu254Pro (c.761T>C) in the general population?

ACE p.Leu254Pro (c.761T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACE p.Leu254Pro (c.761T>C)?

AlphaMissense predicts likely pathogenic (score 0.9944) — an in-silico prediction, not a clinical call.

ACE p.Leu254Pro

c.761T>C · rs2049687627 · VCV890453

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9944 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal tubular dysgenesis

Computational evidence

Protein change
AlphaMissense	0.9944	likely pathogenic · top 1% in ACE
REVEL	0.729	pathogenic-leaning
SaProt	LLR -17.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACE
Protein: p.Leu254Pro
Coding: c.761T>C
MANE Select: NM_000789
dbSNP: rs2049687627
Type: single nucleotide variant
Location: chr17:63480442 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 254: an α-helix; 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

Similar variants

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
ACE c.2739+5G>A Uncertain significance ★★ same condition
ACE p.Ala730Glu Uncertain significance ★★ ⚠ 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-leu254pro (accessed [today's date]).

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