Is ACKR4 p.Met281Val (c.841A>G) pathogenic?

ACKR4 p.Met281Val (c.841A>G) is classified Uncertain significance in ACKR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.1695); Ultra-rare (popmax 0.0281%, nfe).

How common is ACKR4 p.Met281Val (c.841A>G) in the general population?

ACKR4 p.Met281Val (c.841A>G) is ultra-rare (popmax 0.0281%, nfe) (gnomAD).

What do computational predictors say about ACKR4 p.Met281Val (c.841A>G)?

AlphaMissense predicts likely benign (score 0.1695) — an in-silico prediction, not a clinical call.

ACKR4 p.Met281Val

c.841A>G · rs368529492 · VCV2226977

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1695 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0281%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1695	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -6.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.4	GERP 0.095, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 337 bp · p 5.7e-25 · regional, not allelic
Overall
CADD	14.46	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0281% European (non-Finnish) · 332/1,179,762 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.0216% 348/1,613,736 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0281%	3,553
Remaining individualsnot grpmax-eligible	0.016%	6,246
African / African-American	0.00534%	18,724
Admixed American	0.00167%	59,994
Finnishnot grpmax-eligible	0.00156%	64,050

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: ACKR4
Protein: p.Met281Val
Coding: c.841A>G
MANE Select: NM_032169 · reported on NM_016557
dbSNP: rs368529492
Type: single nucleotide variant
Location: chr3:132601238 (GRCh38)

Full ACKR4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/ackr4-p-met281val (accessed [today's date]).

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