Is CDH5 p.Arg622Gln (c.1865G>A) pathogenic?

CDH5 p.Arg622Gln (c.1865G>A) is classified Uncertain significance in CDH5 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-04-20). AlphaMissense: likely benign (0.1213); Ultra-rare (popmax 0.0122%, nfe).

How common is CDH5 p.Arg622Gln (c.1865G>A) in the general population?

CDH5 p.Arg622Gln (c.1865G>A) is ultra-rare (popmax 0.0122%, nfe) (gnomAD).

What do computational predictors say about CDH5 p.Arg622Gln (c.1865G>A)?

AlphaMissense predicts likely benign (score 0.1213) — an in-silico prediction, not a clinical call.

CDH5 p.Arg622Gln

c.1865G>A · rs139612718 · VCV2688754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1213 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1213	likely benign
REVEL	0.533	indeterminate
SaProt	LLR -6.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.49	acceptor gain · deltas
Pangolin	Δ0.23	gain · loss 0.08 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 24 kb · p 0.00013 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0122% European (non-Finnish) · 144/1,176,550 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00997%

Overall 0.00954% 153/1,603,670 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0122%	8,170
African / African-American	0.0067%	14,933
Remaining individualsnot grpmax-eligible	0.00323%	30,913
Finnishnot grpmax-eligible	0.00161%	61,940
South Asian	0.00111%	89,968

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: CDH5
Protein: p.Arg622Gln
Coding: c.1865G>A
MANE Select: NM_001795
dbSNP: rs139612718
Type: single nucleotide variant
Location: chr16:66402679 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.46
Residue 622: the 'required for interaction with pals1' region

Full CDH5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH5 p.Arg622Trp Uncertain significance ★ ⚠ same residue
CDH5 p.Val266= Benign ★★ same type
CDH5 p.Ala13Ser Uncertain significance ★ ⚠ same type
CDH5 p.Ala187Val Uncertain significance ★ ⚠ same type
CDH5 p.Ala201Ser Uncertain significance ★ ⚠ same type
CDH5 p.Ala21Thr Uncertain significance ★ ⚠ same type
CDH5 p.Ala229Val Uncertain significance ★ ⚠ same type
CDH5 p.Ala353Val 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/cdh5-p-arg622gln (accessed [today's date]).

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