Is CD101 p.Arg548His (c.1643G>A) pathogenic?

CD101 p.Arg548His (c.1643G>A) is classified Uncertain significance in CD101 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.239); Very rare (popmax 0.00222%, sas).

How common is CD101 p.Arg548His (c.1643G>A) in the general population?

CD101 p.Arg548His (c.1643G>A) is very rare (popmax 0.00222%, sas) (gnomAD).

What do computational predictors say about CD101 p.Arg548His (c.1643G>A)?

AlphaMissense predicts likely benign (score 0.239) — an in-silico prediction, not a clinical call.

CD101 p.Arg548His

c.1643G>A · VCV4222491

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.239 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00222%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.239	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -6.55	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 7.6	GERP 0.84, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.034 · regional, not allelic
Overall
CADD	25.4	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 0.00222% South Asian · 2/90,166 alleles

Filtering AF 0.000368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000748% 12/1,605,022 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00222%	45,083
African / African-American	0.00134%	74,676
European (non-Finnish)	0.000766%	130,471

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.Arg548His
Coding: c.1643G>A
MANE Select: NM_001256106
Type: single nucleotide variant
Location: chr1:117018186 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.76
Residue 548: the ig-like c2-type 5 domain

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

Similar variants

CD101 p.Arg548Cys 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-arg548his (accessed [today's date]).

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