Is CD93 p.Pro541Ser (c.1621C>T) pathogenic?

CD93 p.Pro541Ser (c.1621C>T) is classified Benign/Likely benign in CD93 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-28). AlphaMissense: likely benign (0.0744); Common (popmax 67.7%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CD93 p.Pro541Ser (c.1621C>T)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

CD93 p.Pro541Ser

Q: How common is CD93 p.Pro541Ser (c.1621C>T) in the general population?

CD93 p.Pro541Ser (c.1621C>T) is common (popmax 67.7%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1621C>T · rs3746731 · VCV2688535

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 67.7%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -6.65	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 1.7	GERP -1.8, phastCons 0.92
Regional constraint	o/e 1.09	unconstrained · MANE · 2,239 bp · p 0.011 · regional, not allelic
Overall
CADD	8.393	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 67.7% Middle Eastern · 4,104/6,062 alleles

Filtering AF 66% ClinGen BA1/BS1 input FAF95, joint · FAF99 65.3%

Overall 55.3% 892,594/1,613,292 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	78.8%	1
Middle Easterngrpmax	67.7%	1
East Asian	65.8%	2
Ashkenazi Jewishnot grpmax-eligible	64.5%	2
South Asian	64.5%	2
Admixed American	63.3%	2
Remaining individualsnot grpmax-eligible	56.3%	2
European (non-Finnish)	55.5%	2
Finnishnot grpmax-eligible	39.1%	3
African / African-American	37.3%	3

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CD93
Protein: p.Pro541Ser
Coding: c.1621C>T
MANE Select: NM_012072
dbSNP: rs3746731
Type: single nucleotide variant
Location: chr20:23084572 (GRCh38)
Gene constraint: LOEUF 1.237 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.07 · 2 PDB
Residue 541: the 'disordered' region; a UniProt-annotated variant site (in)

Full CD93 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD93 p.Arg496= Benign/Likely benign ★★ same type
CD93 p.Gly448= Benign ★★ same type
CD93 p.His551= Likely benign ★★ same type
CD93 p.Ser520Leu Benign ★★ same type
CD93 p.Thr493Ile Benign/Likely benign ★★ ⚠ same type
CD93 p.Val428Leu Benign ★★ same type
CD93 p.Ala214Val Uncertain significance ★ ⚠ same type
CD93 p.Ala24Pro 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/cd93-p-pro541ser (accessed [today's date]).

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