Is CD101 p.Arg216Trp (c.646C>T) pathogenic?

CD101 p.Arg216Trp (c.646C>T) is classified Uncertain significance in CD101 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-26). AlphaMissense: ambiguous (0.3798); Ultra-rare (popmax 0.011%, sas).

How common is CD101 p.Arg216Trp (c.646C>T) in the general population?

CD101 p.Arg216Trp (c.646C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about CD101 p.Arg216Trp (c.646C>T)?

AlphaMissense predicts ambiguous (score 0.3798) — an in-silico prediction, not a clinical call.

CD101 p.Arg216Trp

c.646C>T · rs374093963 · VCV3140268

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3798 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Computational evidence

Protein change
AlphaMissense	0.3798	ambiguous
REVEL	0.616	indeterminate
SaProt	LLR -12.30	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 0.53, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.034 · regional, not allelic
Overall
CADD	24.3	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 0.011% South Asian · 10/91,080 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00136% 22/1,614,008 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
African / African-American	0.00668%	14,981
European (non-Finnish)	0.000593%	168,575

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.Arg216Trp
Coding: c.646C>T
MANE Select: NM_001256106
dbSNP: rs374093963
Type: single nucleotide variant
Location: chr1:117011771 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.76
Residue 216: a disulfide bond; the ig-like c2-type 2 domain

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

Similar variants

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
CD101 p.Ala195Thr 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/cd101-p-arg216trp (accessed [today's date]).

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