Is ACE p.Ser68Arg (c.204C>G) pathogenic?

ACE p.Ser68Arg (c.204C>G) is classified Uncertain significance in ACE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-22). AlphaMissense: likely pathogenic (0.6077); Ultra-rare (popmax 0.016%, amr).

How common is ACE p.Ser68Arg (c.204C>G) in the general population?

ACE p.Ser68Arg (c.204C>G) is ultra-rare (popmax 0.016%, amr) (gnomAD).

What do computational predictors say about ACE p.Ser68Arg (c.204C>G)?

AlphaMissense predicts likely pathogenic (score 0.6077) — an in-silico prediction, not a clinical call.

ACE p.Ser68Arg

c.204C>G · rs1170287329 · VCV1423689

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6077 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6077	likely pathogenic
REVEL	0.265	benign-leaning
SaProt	LLR -8.79	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.57	donor gain · deltas
Constraint at this position
Conservation	phyloP 1.4	GERP -1.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	24.9	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 0.016% Admixed American · 7/43,798 alleles

Filtering AF 0.00742% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00256% 37/1,442,664 alleles · ultra-rare exomes 36/1,292,034 · genomes 1/150,630 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.016%	6,257
Remaining individualsnot grpmax-eligible	0.0037%	27,020
South Asian	0.00278%	36,034
European (non-Finnish)	0.00229%	43,689
African / African-American	0.00147%	67,992

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.Ser68Arg
Coding: c.204C>G
MANE Select: NM_000789
dbSNP: rs1170287329
Type: single nucleotide variant
Location: chr17:63477298 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB
Residue 68: 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 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-ser68arg (accessed [today's date]).

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