Is CCN6 p.Pro59Ser (c.175C>T) pathogenic?

CCN6 p.Pro59Ser (c.175C>T) is classified Uncertain significance in CCN6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-20). AlphaMissense: likely benign (0.1334); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with CCN6 p.Pro59Ser (c.175C>T)?

CCN6 p.Pro59Ser (c.175C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CCN6 p.Pro59Ser (c.175C>T) in the general population?

CCN6 p.Pro59Ser (c.175C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CCN6 p.Pro59Ser (c.175C>T)?

AlphaMissense predicts likely benign (score 0.1334) — an in-silico prediction, not a clinical call.

CCN6 p.Pro59Ser

c.175C>T · rs991418553 · VCV1967964

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1334 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1334	likely benign
REVEL	0.333	indeterminate
SaProt	LLR -10.10	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 15 kb · p 0.028 · regional, not allelic
Overall
CADD	23.6	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 0.00333% Admixed American · 2/59,992 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000372% 6/1,614,004 alleles · very rare exomes 4/1,461,880 · genomes 2/152,124 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,996
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00134%	74,896
European (non-Finnish)	0.000169%	590,016

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: CCN6
Protein: p.Pro59Ser
Coding: c.175C>T
MANE Select: NM_198239
dbSNP: rs991418553
Type: single nucleotide variant
Location: chr6:112061117 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.30
Residue 59: a UniProt-annotated variant site (in pprd); the igfbp n-terminal domain

Full CCN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CCN6 p.Cys337Tyr Pathogenic/Likely pathogenic ★★ same condition
CCN6 p.Ala15Thr Uncertain significance ★★ ⚠ same condition
CCN6 p.Asp253Asn Uncertain significance ★★ ⚠ same condition
CCN6 p.Gln133Glu Uncertain significance ★★ ⚠ same condition
CCN6 p.Gln289His Uncertain significance ★★ ⚠ same condition
CCN6 p.Glu123Lys Uncertain significance ★★ ⚠ same condition
CCN6 p.Lys173Glu Uncertain significance ★★ ⚠ same condition
CCN6 p.Lys206Glu Uncertain significance ★★ ⚠ same condition

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/ccn6-p-pro59ser (accessed [today's date]).

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