Is ACE p.Leu1024Phe (c.3070C>T) pathogenic?

ACE p.Leu1024Phe (c.3070C>T) is classified Uncertain significance in ACE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-18). AlphaMissense: likely pathogenic (0.7288); Ultra-rare (popmax 0.0178%, eas); Associated with ACE-related disorder.

What condition is associated with ACE p.Leu1024Phe (c.3070C>T)?

ACE p.Leu1024Phe (c.3070C>T) is associated with ACE-related disorder (ClinVar).

How common is ACE p.Leu1024Phe (c.3070C>T) in the general population?

ACE p.Leu1024Phe (c.3070C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about ACE p.Leu1024Phe (c.3070C>T)?

AlphaMissense predicts likely pathogenic (score 0.7288) — an in-silico prediction, not a clinical call.

ACE p.Leu1024Phe

c.3070C>T · VCV3764603

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7288 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ACE-related disorder

Computational evidence

Protein change
AlphaMissense	0.7288	likely pathogenic
REVEL	0.458	indeterminate
SaProt	LLR -11.03	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	24.3	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

Grpmax group 0.0178% East Asian · 8/44,892 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00062% 10/1,614,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,612
South Asian	0.0022%	45,544

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.Leu1024Phe
Coding: c.3070C>T
MANE Select: NM_000789
Type: single nucleotide variant
Location: chr17:63493593 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 1024: an α-helix; the peptidase m2 2 domain

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

Disease context

ACE-related disorder

Similar variants

ACE p.Arg265Ter Pathogenic ★★ same condition
ACE p.Arg496Gln Likely pathogenic ★★ same condition
ACE p.Lys571Asn Uncertain significance ★★ ⚠ same condition
ACE p.Val978Met Uncertain significance ★★ ⚠ same condition
ACE c.3503+1G>A Pathogenic ★ same condition
ACE p.Gln116Ter Likely pathogenic ★ same condition
ACE p.Gln63Ter Likely pathogenic ★ same condition
ACE c.1922-199C>T 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-leu1024phe (accessed [today's date]).

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