Is CD68 p.Leu196Pro (c.587T>C) pathogenic?

CD68 p.Leu196Pro (c.587T>C) is classified Uncertain significance in CD68 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely pathogenic (0.6701); Ultra-rare (popmax 0.0567%, amr).

How common is CD68 p.Leu196Pro (c.587T>C) in the general population?

CD68 p.Leu196Pro (c.587T>C) is ultra-rare (popmax 0.0567%, amr) (gnomAD).

What do computational predictors say about CD68 p.Leu196Pro (c.587T>C)?

AlphaMissense predicts likely pathogenic (score 0.6701) — an in-silico prediction, not a clinical call.

CD68 p.Leu196Pro

c.587T>C · VCV4222990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6701 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0567%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6701	likely pathogenic · top 9% in CD68
REVEL	0.537	indeterminate
SaProt	LLR -11.20	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,830 bp · p 0.38 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0567% Admixed American · 34/59,994 alleles

Filtering AF 0.0416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.00254% 41/1,614,010 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0567%	1,765
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.000424%	236,005

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: CD68
Protein: p.Leu196Pro
Coding: c.587T>C
MANE Select: NM_001251
Type: single nucleotide variant
Location: chr17:7580485 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.23
Residue 196: a disulfide bond

Full CD68 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD68 p.Ile329Thr Benign ★★ same type
CD68 p.Ala10Val Uncertain significance ★ ⚠ same type
CD68 p.Ala262Thr Uncertain significance ★ ⚠ same type
CD68 p.Ala269Val Uncertain significance ★ ⚠ same type
CD68 p.Ala299Asp Uncertain significance ★ ⚠ same type
CD68 p.Ala99Thr Uncertain significance ★ ⚠ same type
CD68 p.Arg345Pro Uncertain significance ★ ⚠ same type
CD68 p.Arg345Trp 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/cd68-p-leu196pro (accessed [today's date]).

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