Is CCL22 p.Arg44His (c.131G>A) pathogenic?

CCL22 p.Arg44His (c.131G>A) is classified Uncertain significance in CCL22 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-23). AlphaMissense: likely benign (0.1595); Ultra-rare (popmax 0.0987%, mid).

How common is CCL22 p.Arg44His (c.131G>A) in the general population?

CCL22 p.Arg44His (c.131G>A) is ultra-rare (popmax 0.0987%, mid) (gnomAD).

What do computational predictors say about CCL22 p.Arg44His (c.131G>A)?

AlphaMissense predicts likely benign (score 0.1595) — an in-silico prediction, not a clinical call.

CCL22 p.Arg44His

c.131G>A · VCV3264473

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1595 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0987%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1595	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -6.52	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 2.2	GERP 0.14, phastCons 0.011
Regional constraint	o/e 0.92	unconstrained · MANE · 4,768 bp · p 0.39 · regional, not allelic
Overall
CADD	21.4	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 0.0987% Middle Eastern · 6/6,082 alleles

Filtering AF 0.0429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.00248% 40/1,614,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0987%	1,014
South Asian	0.0154%	6,507
African / African-American	0.00534%	18,733
Admixed American	0.00333%	29,998
Remaining individualsnot grpmax-eligible	0.0032%	31,244
East Asian	0.00223%	44,898
Finnishnot grpmax-eligible	0.00156%	64,026
European (non-Finnish)	0.000847%	118,003

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: CCL22
Protein: p.Arg44His
Coding: c.131G>A
MANE Select: NM_002990
Type: single nucleotide variant
Location: chr16:57360494 (GRCh38)
Gene constraint: LOEUF 1.634 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.21
Residue 44: a disulfide bond

Full CCL22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCL22 p.Tyr40His Likely benign ★★ ⚠ same type
CCL22 p.Arg38Cys Uncertain significance ★ ⚠ same type
CCL22 p.Arg38His Uncertain significance ★ ⚠ same type
CCL22 p.Arg3Cys Uncertain significance ★ ⚠ same type
CCL22 p.Arg42His Uncertain significance ★ ⚠ same type
CCL22 p.Arg48Cys Uncertain significance ★ ⚠ same type
CCL22 p.Arg48His Uncertain significance ★ ⚠ same type
CCL22 p.Asp78Asn 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/ccl22-p-arg44his (accessed [today's date]).

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