Is ACE2 p.Ser646Phe (c.1937C>T) pathogenic?

ACE2 p.Ser646Phe (c.1937C>T) is classified Uncertain significance in ACE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-14). AlphaMissense: ambiguous (0.3626); Absent from gnomAD v4.1.

How common is ACE2 p.Ser646Phe (c.1937C>T) in the general population?

ACE2 p.Ser646Phe (c.1937C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACE2 p.Ser646Phe (c.1937C>T)?

AlphaMissense predicts ambiguous (score 0.3626) — an in-silico prediction, not a clinical call.

ACE2 p.Ser646Phe

c.1937C>T · rs2519671882 · VCV2312004

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3626 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.3626	ambiguous
REVEL	0.478	indeterminate
SaProt	LLR -5.13	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.21	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 8.6	GERP 0.74, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 39 kb · p 0.0023 · regional, not allelic
Overall
CADD	24.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACE2
Protein: p.Ser646Phe
Coding: c.1937C>T
MANE Select: NM_001371415
dbSNP: rs2519671882
Type: single nucleotide variant
Location: chrX:15567786 (GRCh38)
Structure: AlphaFold pLDDT 91.13 · 328 PDB
Residue 646: an α-helix; 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-ser646phe (accessed [today's date]).

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