Is CD163 p.His754Arg (c.2261A>G) pathogenic?

CD163 p.His754Arg (c.2261A>G) is classified Uncertain significance in CD163 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-18). AlphaMissense: likely benign (0.0667); Very rare (popmax 0.00246%, nfe).

How common is CD163 p.His754Arg (c.2261A>G) in the general population?

CD163 p.His754Arg (c.2261A>G) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about CD163 p.His754Arg (c.2261A>G)?

AlphaMissense predicts likely benign (score 0.0667) — an in-silico prediction, not a clinical call.

CD163 p.His754Arg

c.2261A>G · VCV3829361

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0667 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0667	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -4.76	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 0.49	GERP 0.73, phastCons 0.23
Regional constraint	o/e 0.77	unconstrained · MANE · 24 kb · p 1.4e-17 · regional, not allelic
Overall
CADD	8.447	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 0.00246% European (non-Finnish) · 29/1,180,026 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00192% 31/1,614,050 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00246%	40,691
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00133%	74,920

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: CD163
Protein: p.His754Arg
Coding: c.2261A>G
MANE Select: NM_203416
Type: single nucleotide variant
Location: chr12:7486696 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.72 · 14 PDB
Residue 754: the srcr 7 domain; an α-helix; a disulfide bond

Full CD163 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD163 c.3344-24C>A Benign ★★ same type
CD163 c.3344-56G>A Likely benign ★★ same type
CD163 c.457+9T>A Benign ★★ same type
CD163 p.Asn642Lys Benign ★★ same type
CD163 p.Asn892= Benign ★★ same type
CD163 p.Cys1008= Benign ★★ same type
CD163 p.Ile342Val Benign ★★ ⚠ same type
CD163 p.Leu867= 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/cd163-p-his754arg (accessed [today's date]).

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