Is ACKR1 p.Phe65Leu (c.193T>C) pathogenic?

ACKR1 p.Phe65Leu (c.193T>C) is classified Uncertain significance in ACKR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-03). AlphaMissense: likely pathogenic (0.9253); Very rare (popmax 0.00133%, afr).

How common is ACKR1 p.Phe65Leu (c.193T>C) in the general population?

ACKR1 p.Phe65Leu (c.193T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACKR1 p.Phe65Leu (c.193T>C)?

AlphaMissense predicts likely pathogenic (score 0.9253) — an in-silico prediction, not a clinical call.

ACKR1 p.Phe65Leu

c.193T>C · VCV3998544

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9253 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9253	likely pathogenic · top 2% in ACKR1
REVEL	0.322	indeterminate
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,487 bp · p 0.031 · regional, not allelic
Overall
CADD	23.0	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 0.00133% African / African-American · 1/74,940 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00062% 10/1,614,082 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,940
South Asian	0.0011%	91,088
European (non-Finnish)	0.000678%	147,504

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: ACKR1
Protein: p.Phe65Leu
Coding: c.193T>C
MANE Select: NM_002036
Type: single nucleotide variant
Location: chr1:159205632 (GRCh38)
Gene constraint: LOEUF 1.841 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 78.25 · 6 PDB
Residue 65: a disulfide bond

Full ACKR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACKR1 p.Arg89Cys Likely benign ★★ same type
ACKR1 p.Gly238= Benign ★★ same type
ACKR1 p.Gly42Asp Benign ★★ same type
ACKR1 p.Ala144Pro Uncertain significance ★ ⚠ same type
ACKR1 p.Ala49Val Uncertain significance ★ ⚠ same type
ACKR1 p.Asn244Ser Uncertain significance ★ ⚠ same type
ACKR1 p.Asp283Gly Uncertain significance ★ ⚠ same type
ACKR1 p.Cys51Trp 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/ackr1-p-phe65leu (accessed [today's date]).

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