Is ACE p.Leu273Phe (c.817C>T) pathogenic?

ACE p.Leu273Phe (c.817C>T) is classified Conflicting classifications of pathogenicity in ACE (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-01-13). AlphaMissense: likely benign (0.3363); Very rare (popmax 0.0011%, sas); Associated with microvascular complications of diabetes, susceptibility to, 3.

What condition is associated with ACE p.Leu273Phe (c.817C>T)?

ACE p.Leu273Phe (c.817C>T) is associated with microvascular complications of diabetes, susceptibility to, 3, renal tubular dysgenesis of genetic origin, hemorrhage, intracerebral, susceptibility to (ClinVar).

How common is ACE p.Leu273Phe (c.817C>T) in the general population?

ACE p.Leu273Phe (c.817C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ACE p.Leu273Phe (c.817C>T)?

AlphaMissense predicts likely benign (score 0.3363) — an in-silico prediction, not a clinical call.

ACE p.Leu273Phe

c.817C>T · rs1357918249 · VCV432142

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3363 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

microvascular complications of diabetes, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.3363	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -11.27	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,644 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,086
European (non-Finnish)	0.000254%	393,343

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.Leu273Phe
Coding: c.817C>T
MANE Select: NM_000789
dbSNP: rs1357918249
Type: single nucleotide variant
Location: chr17:63480498 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 273: the peptidase m2 1 domain

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

Disease context

microvascular complications of diabetes, susceptibility to, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal tubular dysgenesis of genetic origin hemorrhage, intracerebral, susceptibility to

Similar variants

ACE p.Leu273= Likely benign ★ 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-leu273phe (accessed [today's date]).

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