Is CCL8 p.Val74Phe (c.220G>T) pathogenic?

CCL8 p.Val74Phe (c.220G>T) is classified Uncertain significance in CCL8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-19). AlphaMissense: likely benign (0.1266); Ultra-rare (popmax 0.0175%, afr).

How common is CCL8 p.Val74Phe (c.220G>T) in the general population?

CCL8 p.Val74Phe (c.220G>T) is ultra-rare (popmax 0.0175%, afr) (gnomAD).

What do computational predictors say about CCL8 p.Val74Phe (c.220G>T)?

AlphaMissense predicts likely benign (score 0.1266) — an in-silico prediction, not a clinical call.

CCL8 p.Val74Phe

c.220G>T · VCV3997512

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1266 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1266	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -8.73	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 -1	GERP -3.8
Regional constraint	o/e 1.08	unconstrained · MANE · 1,402 bp · p 0.41 · regional, not allelic
Overall
CADD	0.432	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 0.0175% African / African-American · 13/74,492 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00817%

Overall 0.000808% 13/1,608,220 alleles · ultra-rare

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: CCL8
Protein: p.Val74Phe
Coding: c.220G>T
MANE Select: NM_005623
Type: single nucleotide variant
Location: chr17:34320827 (GRCh38)
Gene constraint: LOEUF 1.794 · pLI 0.22 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 3 PDB
Residue 74: a β-strand; a disulfide bond

Full CCL8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCL8 p.Ala14Val Benign ★★ same type
CCL8 p.Ile57= Benign ★★ same type
CCL8 p.Leu8= Benign ★★ same type
CCL8 p.Ser29= Benign ★★ same type
CCL8 p.Ala15Val Uncertain significance ★ ⚠ same type
CCL8 p.Ala23Ser Uncertain significance ★ ⚠ same type
CCL8 p.Ala5Thr Uncertain significance ★ ⚠ same type
CCL8 p.Arg53Gly 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/ccl8-p-val74phe (accessed [today's date]).

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