Is CD6 p.Leu596Pro (c.1787T>C) pathogenic?

CD6 p.Leu596Pro (c.1787T>C) is classified Likely benign in CD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.0605); Very rare (popmax 0.000339%, nfe).

How common is CD6 p.Leu596Pro (c.1787T>C) in the general population?

CD6 p.Leu596Pro (c.1787T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CD6 p.Leu596Pro (c.1787T>C)?

AlphaMissense predicts likely benign (score 0.0605) — an in-silico prediction, not a clinical call.

CD6 p.Leu596Pro

c.1787T>C · VCV4222976

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0605 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0605	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -5.53	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 -3	GERP -2.9
Regional constraint	o/e 0.86	unconstrained · MANE · 47 kb · p 2.2e-05 · regional, not allelic
Overall
CADD	0.043	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 0.000339% European (non-Finnish) · 4/1,179,996 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000411% 6/1,460,988 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,236
European (non-Finnish)grpmax	0.000339%	294,999

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CD6
Protein: p.Leu596Pro
Coding: c.1787T>C
MANE Select: NM_006725
Type: single nucleotide variant
Location: chr11:61017963 (GRCh38)
Gene constraint: LOEUF 1.03 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.14 · 1 PDB
Residue 596: the 'disordered' region

Full CD6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD6 p.Ala151Val Uncertain significance ★ ⚠ same type
CD6 p.Ala160Val Uncertain significance ★ ⚠ same type
CD6 p.Ala22Asp Uncertain significance ★ ⚠ same type
CD6 p.Ala235Thr Uncertain significance ★ ⚠ same type
CD6 p.Ala311Glu Uncertain significance ★ ⚠ same type
CD6 p.Ala431Asp Uncertain significance ★ ⚠ same type
CD6 p.Ala78Thr Uncertain significance ★ ⚠ same type
CD6 p.Arg220Ser 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/cd6-p-leu596pro (accessed [today's date]).

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