Is ACE p.Phe842Ser (c.2525T>C) pathogenic?

ACE p.Phe842Ser (c.2525T>C) is classified Uncertain significance in ACE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-09). AlphaMissense: likely pathogenic (0.6295); Very rare (popmax 0.00133%, afr).

How common is ACE p.Phe842Ser (c.2525T>C) in the general population?

ACE p.Phe842Ser (c.2525T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACE p.Phe842Ser (c.2525T>C)?

AlphaMissense predicts likely pathogenic (score 0.6295) — an in-silico prediction, not a clinical call.

ACE p.Phe842Ser

c.2525T>C · VCV3698254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6295 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6295	likely pathogenic
REVEL	0.216	benign-leaning
SaProt	LLR -8.17	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.53	GERP -3.2, phastCons 0.09
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	20.1	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 0.00133% African / African-American · 1/75,046 alleles

Overall 6.2e-05% 1/1,614,122 alleles · very rare exomes 0/1,461,834 · genomes 1/152,288 · joint denominator

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.Phe842Ser
Coding: c.2525T>C
MANE Select: NM_000789
Type: single nucleotide variant
Location: chr17:63489016 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 842: an α-helix; the peptidase m2 2 domain

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

Similar variants

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
ACE p.Arg508Ter 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-phe842ser (accessed [today's date]).

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