Is ACKR3 p.Pro153Ser (c.457C>T) pathogenic?

ACKR3 p.Pro153Ser (c.457C>T) is classified Likely benign in ACKR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely benign (0.0753); Ultra-rare (popmax 0.0567%, amr).

How common is ACKR3 p.Pro153Ser (c.457C>T) in the general population?

ACKR3 p.Pro153Ser (c.457C>T) is ultra-rare (popmax 0.0567%, amr) (gnomAD).

What do computational predictors say about ACKR3 p.Pro153Ser (c.457C>T)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

ACKR3 p.Pro153Ser

c.457C>T · VCV3998563

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0567%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -5.70	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 0.14	GERP -3.8, phastCons 0.011
Regional constraint	o/e 0.83	unconstrained · MANE · 1,085 bp · p 0.00028 · regional, not allelic
Overall
CADD	2.575	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 0.0567% Admixed American · 34/60,002 alleles

Filtering AF 0.0416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.0026% 42/1,614,080 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0567%	1,765
Remaining individualsnot grpmax-eligible	0.0064%	15,623
European (non-Finnish)	0.000339%	295,011

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: ACKR3
Protein: p.Pro153Ser
Coding: c.457C>T
MANE Select: NM_020311
Type: single nucleotide variant
Location: chr2:236580922 (GRCh38)
Gene constraint: LOEUF 0.492 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 82.47 · 14 PDB
Residue 153: a disulfide bond

Full ACKR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACKR3 p.Ile210= Benign ★★ same type
ACKR3 p.Pro201= Benign ★★ same type
ACKR3 p.Val230Ile Benign ★★ same type
ACKR3 p.Ala229Gly Uncertain significance ★ ⚠ same type
ACKR3 p.Ala241Val Uncertain significance ★ ⚠ same type
ACKR3 p.Ala296Thr Uncertain significance ★ ⚠ same type
ACKR3 p.Arg162Cys Uncertain significance ★ ⚠ same type
ACKR3 p.Arg288Trp 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/ackr3-p-pro153ser (accessed [today's date]).

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