Is ACE2 p.Ala614Ser (c.1840G>T) pathogenic?

ACE2 p.Ala614Ser (c.1840G>T) is classified Likely benign in ACE2 (ClinVar, No assertion criteria, 2 submitters). AlphaMissense: likely benign (0.0672); Ultra-rare (popmax 0.0373%, nfe).

How common is ACE2 p.Ala614Ser (c.1840G>T) in the general population?

ACE2 p.Ala614Ser (c.1840G>T) is ultra-rare (popmax 0.0373%, nfe) (gnomAD).

What do computational predictors say about ACE2 p.Ala614Ser (c.1840G>T)?

AlphaMissense predicts likely benign (score 0.0672) — an in-silico prediction, not a clinical call.

ACE2 p.Ala614Ser

c.1840G>T · rs201715513 · VCV1284944

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0672 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0672	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -3.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.6	GERP -3.1
Regional constraint	o/e 0.87	unconstrained · MANE · 39 kb · p 0.0023 · regional, not allelic
Overall
CADD	0.017	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 0.0373% European (non-Finnish) · 333/893,136 alleles

Filtering AF 0.0339% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0326%

Overall 0.031% 375/1,208,019 alleles · ultra-rare exomes 364/1,095,310 · genomes 11/112,709 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0557%	1,795
European (non-Finnish)grpmax	0.0373%	2,682
Remaining individualsnot grpmax-eligible	0.0316%	3,167
African / African-American	0.00174%	57,369

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ACE2
Protein: p.Ala614Ser
Coding: c.1840G>T
MANE Select: NM_001371415
dbSNP: rs201715513
Type: single nucleotide variant
Location: chrX:15570351 (GRCh38)
Structure: AlphaFold pLDDT 91.13 · 328 PDB
Residue 614: a turn; the collectrin-like domain

Full ACE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACE2 c.584-7C>A Likely benign ★★ same type
ACE2 p.Asn690= Benign ★★ same type
ACE2 p.Lys26Arg Likely benign ★★ same type
BMX p.Ala214Val Benign ★★ same type
ACE2 c.2309+2T>A Uncertain significance ★ same type
ACE2 p.Arg161Lys Uncertain significance ★ ⚠ same type
ACE2 p.Asn277Asp Uncertain significance ★ ⚠ same type
ACE2 p.Asn682Ser Uncertain significance ★ ⚠ 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/ace2-p-ala614ser (accessed [today's date]).

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