Is CD101 p.Arg654His (c.1961G>A) pathogenic?

CD101 p.Arg654His (c.1961G>A) is classified Likely benign in CD101 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-23). AlphaMissense: likely benign (0.0647); Rare (popmax 0.149%, mid).

How common is CD101 p.Arg654His (c.1961G>A) in the general population?

CD101 p.Arg654His (c.1961G>A) is rare (popmax 0.149%, mid) (gnomAD).

What do computational predictors say about CD101 p.Arg654His (c.1961G>A)?

AlphaMissense predicts likely benign (score 0.0647) — an in-silico prediction, not a clinical call.

CD101 p.Arg654His

c.1961G>A · rs763269950 · VCV2464739

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0647 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0647	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -6.42	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 1.2	GERP -3.2
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.034 · regional, not allelic
Overall
CADD	2.225	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 0.149% Middle Eastern · 9/6,058 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0579%

Overall 0.00607% 98/1,613,258 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.149%	673
East Asian	0.0156%	6,408
African / African-American	0.012%	8,335
South Asian	0.011%	9,104
Admixed American	0.01%	10,000
European (non-Finnish)	0.00466%	21,442
Remaining individualsnot grpmax-eligible	0.0032%	31,240

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: CD101
Protein: p.Arg654His
Coding: c.1961G>A
MANE Select: NM_001256106
dbSNP: rs763269950
Type: single nucleotide variant
Location: chr1:117018504 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.76

Full CD101 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD101 p.Arg654Cys Uncertain significance ★ ⚠ same residue
CD101 p.Arg622His Benign ★★ same type
CD101 p.Arg933Gln Benign ★★ ⚠ same type
CD101 p.Asn225Ser Benign ★★ same type
CD101 p.Leu362Pro Benign ★★ same type
CD101 p.Ser525Arg Benign ★★ ⚠ same type
CD101 p.Ser985= Benign ★★ same type
CD101 p.Tyr651Asp Benign ★★ 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/cd101-p-arg654his (accessed [today's date]).

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