Is CD33 p.Ser305Pro (c.913T>C) pathogenic?

CD33 p.Ser305Pro (c.913T>C) is classified Benign in CD33 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-06-10). AlphaMissense: likely benign (0.0487); Common (popmax 30.3%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CD33 p.Ser305Pro (c.913T>C)?

AlphaMissense predicts likely benign (score 0.0487) — an in-silico prediction, not a clinical call.

CD33 p.Ser305Pro

Q: How common is CD33 p.Ser305Pro (c.913T>C) in the general population?

CD33 p.Ser305Pro (c.913T>C) is common (popmax 30.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.913T>C · rs61736475 · VCV1295125

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0487 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 30.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0487	likely benign
REVEL	0.005	strongly benign-leaning
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -7	GERP -3
Regional constraint	o/e 0.91	unconstrained · MANE · 15 kb · p 0.052 · regional, not allelic
Overall
CADD	0.038	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 30.3% African / African-American · 22,677/74,830 alleles

Filtering AF 30% ClinGen BA1/BS1 input FAF95, joint · FAF99 29.8%

Overall 3.5% 56,431/1,613,040 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	30.3%	3
Middle Eastern	4.77%	21
Remaining individualsnot grpmax-eligible	4.17%	24
Admixed American	3.28%	30
European (non-Finnish)	2.28%	44
South Asian	1.66%	60
Ashkenazi Jewishnot grpmax-eligible	0.801%	125
Finnishnot grpmax-eligible	0.458%	218
Amishnot grpmax-eligible	0.329%	304
East Asian	0.029%	3,451

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: CD33
Protein: p.Ser305Pro
Coding: c.913T>C
MANE Select: NM_001772
dbSNP: rs61736475
Type: single nucleotide variant
Location: chr19:51235665 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.30 · 11 PDB
Residue 305: the 'disordered' region

Full CD33 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD33 p.Asp51Asn Uncertain significance ★★ ⚠ same type
CD33 c.924+295A>G Benign ★★ same type
CD33 c.924+296C>T Benign ★★ same type
CD33 c.924+2T>C Benign ★★ same type
CD33 c.924+469G>C Benign ★★ same type
CD33 c.*201G>C Benign ★★ same type
CD33 p.Ala14Val Benign ★★ ⚠ same type
CD33 p.Ala65Pro 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/cd33-p-ser305pro (accessed [today's date]).

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