Is ACE p.Arg259His (c.776G>A) pathogenic?

ACE p.Arg259His (c.776G>A) is classified Conflicting classifications of pathogenicity in ACE (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-07). AlphaMissense: likely pathogenic (0.798); Ultra-rare (popmax 0.0657%, mid); Associated with renal tubular dysgenesis of genetic origin.

What condition is associated with ACE p.Arg259His (c.776G>A)?

ACE p.Arg259His (c.776G>A) is associated with renal tubular dysgenesis of genetic origin, microvascular complications of diabetes, susceptibility to, 3, hemorrhage, intracerebral, susceptibility to (ClinVar).

How common is ACE p.Arg259His (c.776G>A) in the general population?

ACE p.Arg259His (c.776G>A) is ultra-rare (popmax 0.0657%, mid) (gnomAD).

What do computational predictors say about ACE p.Arg259His (c.776G>A)?

AlphaMissense predicts likely pathogenic (score 0.798) — an in-silico prediction, not a clinical call.

ACE p.Arg259His

c.776G>A · rs370903033 · VCV2499819

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.798 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

renal tubular dysgenesis of genetic origin

Computational evidence

Protein change
AlphaMissense	0.798	likely pathogenic
REVEL	0.568	indeterminate
SaProt	LLR -16.58	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	32.0	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 0.0657% Middle Eastern · 4/6,084 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.000991% 16/1,613,906 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0657%	1,521
Admixed American	0.00167%	59,996
African / African-American	0.00134%	74,900
South Asian	0.0011%	91,086
European (non-Finnish)	0.000763%	131,114

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.Arg259His
Coding: c.776G>A
MANE Select: NM_000789
dbSNP: rs370903033
Type: single nucleotide variant
Location: chr17:63480457 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 259: 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 of genetic origin — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: microvascular complications of diabetes, susceptibility to, 3 hemorrhage, intracerebral, susceptibility to

Similar variants

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
ACE p.Met1Thr 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-arg259his (accessed [today's date]).

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