Is CD5 p.Pro224Leu (c.671C>T) pathogenic?

CD5 p.Pro224Leu (c.671C>T) is classified Benign in CD5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-01-18). AlphaMissense: likely benign (0.0695); Common (popmax 27.7%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CD5 p.Pro224Leu (c.671C>T)?

AlphaMissense predicts likely benign (score 0.0695) — an in-silico prediction, not a clinical call.

CD5 p.Pro224Leu

Q: How common is CD5 p.Pro224Leu (c.671C>T) in the general population?

CD5 p.Pro224Leu (c.671C>T) is common (popmax 27.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.671C>T · rs2241002 · VCV1226331

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0695 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 27.7%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0695	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.70	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 -1.2	GERP -3.1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.00031 · regional, not allelic
Overall
CADD	11.33	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 27.7% African / African-American · 20,756/74,992 alleles

Filtering AF 27.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 27.2%

Overall 17.3% 278,945/1,613,996 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	27.7%	4
Amishnot grpmax-eligible	23.1%	4
European (non-Finnish)	18.2%	6
Remaining individualsnot grpmax-eligible	16.6%	6
South Asian	14.8%	7
Middle Eastern	13.8%	7
Ashkenazi Jewishnot grpmax-eligible	13.8%	7
Admixed American	11.4%	9
Finnishnot grpmax-eligible	8.67%	12
East Asian	5.38%	19

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: CD5
Protein: p.Pro224Leu
Coding: c.671C>T
MANE Select: NM_014207
dbSNP: rs2241002
Type: single nucleotide variant
Location: chr11:61119441 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.32 · 4 PDB
Residue 224: a disulfide bond; a UniProt-annotated variant site (in); the srcr 2 domain

Full CD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD5 p.Ala471Val Benign ★★ same type
CD5 p.Ala295Ser Uncertain significance ★ ⚠ same type
CD5 p.Ala492Asp Uncertain significance ★ ⚠ same type
CD5 p.Ala492Val Uncertain significance ★ ⚠ same type
CD5 p.Ala77Val Uncertain significance ★ ⚠ same type
CD5 p.Arg228Gln Uncertain significance ★ ⚠ same type
CD5 p.Arg338Gln Uncertain significance ★ ⚠ same type
CD5 p.Arg39Cys 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/cd5-p-pro224leu (accessed [today's date]).

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