Is CD101 p.Ile699Phe (c.2095A>T) pathogenic?

CD101 p.Ile699Phe (c.2095A>T) is classified Uncertain significance in CD101 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-24). AlphaMissense: likely benign (0.226); Ultra-rare (popmax 0.0108%, nfe).

How common is CD101 p.Ile699Phe (c.2095A>T) in the general population?

CD101 p.Ile699Phe (c.2095A>T) is ultra-rare (popmax 0.0108%, nfe) (gnomAD).

What do computational predictors say about CD101 p.Ile699Phe (c.2095A>T)?

AlphaMissense predicts likely benign (score 0.226) — an in-silico prediction, not a clinical call.

CD101 p.Ile699Phe

c.2095A>T · rs377288960 · VCV2220199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.226 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.226	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -10.23	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.067	GERP -0.89
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.034 · regional, not allelic
Overall
CADD	16.17	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 0.0108% European (non-Finnish) · 128/1,179,990 alleles

Filtering AF 0.00928% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00871%

Overall 0.00805% 130/1,614,006 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0108%	9,219
African / African-American	0.00267%	37,461

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.Ile699Phe
Coding: c.2095A>T
MANE Select: NM_001256106
dbSNP: rs377288960
Type: single nucleotide variant
Location: chr1:117021650 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.76
Residue 699: the ig-like c2-type 6 domain; a disulfide bond

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-ile699phe (accessed [today's date]).

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