Is CPD p.Lys499Arg (c.1496A>G) pathogenic?

CPD p.Lys499Arg (c.1496A>G) is classified Benign in CPD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-23). AlphaMissense: likely benign (0.0765); Common (popmax 9.97%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CPD p.Lys499Arg (c.1496A>G)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

CPD p.Lys499Arg

Q: How common is CPD p.Lys499Arg (c.1496A>G) in the general population?

CPD p.Lys499Arg (c.1496A>G) is common (popmax 9.97%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1496A>G · rs61743601 · VCV770445

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.97%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -7.06	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 9.3	GERP 1.9, phastCons 1
Overall
CADD	20.2	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 9.97% African / African-American · 7,478/75,014 alleles

Filtering AF 9.78% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.7%

Overall 0.529% 8,546/1,614,076 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.97%	10
Admixed American	0.683%	146
Remaining individualsnot grpmax-eligible	0.618%	162
Middle Eastern	0.215%	466
South Asian	0.022%	4,554
European (non-Finnish)	0.0202%	4,958
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602

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: CPD
Protein: p.Lys499Arg
Coding: c.1496A>G
MANE Select: NM_004839 · reported on NM_001304
dbSNP: rs61743601
Type: single nucleotide variant
Location: chr17:30422862 (GRCh38)
Structure: AlphaFold pLDDT 89.20

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

Similar variants

HOMER2 p.Arg208Cys Uncertain significance ★★ ⚠ same type
HOMER2 p.Arg213Trp Uncertain significance ★★ ⚠ same type
HOMER2 p.Arg215His Uncertain significance ★★ ⚠ same type
HOMER2 p.Arg309Cys Uncertain significance ★★ ⚠ same type
HOMER2 p.Arg334Gln Uncertain significance ★★ ⚠ same type
HOMER2 p.Asn235Lys Uncertain significance ★★ ⚠ same type
HOMER2 p.Glu255Asp Uncertain significance ★★ ⚠ same type
HOMER2 p.Glu274Lys 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/cpd-p-lys499arg (accessed [today's date]).

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