Is ACE p.Leu200Pro (c.599T>C) pathogenic?

ACE p.Leu200Pro (c.599T>C) is classified Uncertain significance in ACE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-05). AlphaMissense: likely pathogenic (0.913); Absent from gnomAD v4.1.

How common is ACE p.Leu200Pro (c.599T>C) in the general population?

ACE p.Leu200Pro (c.599T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACE p.Leu200Pro (c.599T>C)?

AlphaMissense predicts likely pathogenic (score 0.913) — an in-silico prediction, not a clinical call.

ACE p.Leu200Pro

c.599T>C · rs2510684695 · VCV2128434

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.913 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.913	likely pathogenic
REVEL	0.45	indeterminate
SaProt	LLR -12.19	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	25.2	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.Leu200Pro
Coding: c.599T>C
MANE Select: NM_000789
dbSNP: rs2510684695
Type: single nucleotide variant
Location: chr17:63479856 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 200: an α-helix; the peptidase m2 1 domain

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

Similar variants

ACE p.Leu200= Benign/Likely benign ★★ same residue
ACE c.1342+1G>T Likely pathogenic ★★ same type
ACE c.1709+5G>C Pathogenic/Likely pathogenic ★★ same type
ACE c.3503+1G>C Likely pathogenic ★★ same type
ACE c.945+2T>G Likely pathogenic ★★ same type
ACE p.Arg265Ter Pathogenic ★★ same type
ACE p.Arg496Gln Likely pathogenic ★★ same type
ACE p.Arg496Ter Pathogenic/Likely pathogenic ★★ same type

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-leu200pro (accessed [today's date]).

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