Is NCOA3 p.Pro559Ser (c.1675C>T) pathogenic?

NCOA3 p.Pro559Ser (c.1675C>T) is classified Benign in NCOA3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0743); Common (popmax 5.54%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about NCOA3 p.Pro559Ser (c.1675C>T)?

AlphaMissense predicts likely benign (score 0.0743) — an in-silico prediction, not a clinical call.

NCOA3 p.Pro559Ser

Q: How common is NCOA3 p.Pro559Ser (c.1675C>T) in the general population?

NCOA3 p.Pro559Ser (c.1675C>T) is common (popmax 5.54%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1675C>T · rs2230781 · VCV775436

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0743 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.54%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0743	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -4.92	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 2.7	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.93	unconstrained · MANE · 17 kb · p 0.014 · regional, not allelic
Overall
CADD	13.33	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 5.54% African / African-American · 4,153/74,994 alleles

Filtering AF 5.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.34%

Overall 0.295% 4,756/1,614,032 alleles · common exomes 2,276/1,461,870 · genomes 2,480/152,162 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.54%	18
Remaining individualsnot grpmax-eligible	0.397%	252
Admixed American	0.368%	272
Middle Eastern	0.214%	466
European (non-Finnish)	0.00966%	10,351
South Asian	0.00769%	13,011

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: NCOA3
Protein: p.Pro559Ser
Coding: c.1675C>T
MANE Select: NM_181659
dbSNP: rs2230781
Type: single nucleotide variant
Location: chr20:47636061 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.26 · 6 PDB
Residue 559: a UniProt-annotated variant site (in); the 'disordered' region

Full NCOA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RAC3 p.Asp63Asn Pathogenic/Likely pathogenic ★★ same type
RAC3 p.Glu62Lys Pathogenic ★★ same type
RAC3 p.Lys116Asn Pathogenic/Likely pathogenic ★★ same type
RAC3 p.Tyr64Cys Likely pathogenic ★★ same type
RAC3 p.Arg120Cys Uncertain significance ★★ ⚠ same type
RAC3 p.Arg130Gln Uncertain significance ★★ ⚠ same type
RAC3 p.Arg174Cys Uncertain significance ★★ ⚠ same type
NCOA3 p.Pro1351= Likely 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/ncoa3-p-pro559ser (accessed [today's date]).

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