Is ABCC9 p.Pro67Leu (c.200C>T) pathogenic?

ABCC9 p.Pro67Leu (c.200C>T) is classified Uncertain significance in ABCC9 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-28). AlphaMissense: likely pathogenic (0.9394); Very rare (popmax 0.00381%, nfe); Associated with hypertrichotic osteochondrodysplasia Cantu type.

What condition is associated with ABCC9 p.Pro67Leu (c.200C>T)?

ABCC9 p.Pro67Leu (c.200C>T) is associated with hypertrichotic osteochondrodysplasia Cantu type, dilated cardiomyopathy 1O (ClinVar).

How common is ABCC9 p.Pro67Leu (c.200C>T) in the general population?

ABCC9 p.Pro67Leu (c.200C>T) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about ABCC9 p.Pro67Leu (c.200C>T)?

AlphaMissense predicts likely pathogenic (score 0.9394) — an in-silico prediction, not a clinical call.

ABCC9 p.Pro67Leu

c.200C>T · rs766600615 · VCV950045

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9394 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrichotic osteochondrodysplasia Cantu type

Computational evidence

Protein change
AlphaMissense	0.9394	likely pathogenic
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 29 kb · p 4.3e-29 · regional, not allelic
Overall
CADD	31.0	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 0.00381% European (non-Finnish) · 45/1,179,700 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00322% 52/1,613,518 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00801%	12,492
European (non-Finnish)grpmax	0.00381%	26,216
East Asian	0.00223%	44,868
African / African-American	0.00134%	74,866

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: ABCC9
Protein: p.Pro67Leu
Coding: c.200C>T
MANE Select: NM_020297
dbSNP: rs766600615
Type: single nucleotide variant
Location: chr12:21933866 (GRCh38)
Gene constraint: LOEUF 0.557 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.72

Full ABCC9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypertrichotic osteochondrodysplasia Cantu type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1O

Similar variants

ABCC9 p.Pro67= Likely benign ★★ same residue
ABCC9 c.2506-1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC9 p.Arg1116Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCC9 p.Arg1116His Pathogenic ★★ ⚠ same condition
ABCC9 p.Arg1154Gln Pathogenic ★★ same condition
ABCC9 p.Arg1154Trp Pathogenic/Likely pathogenic ★★ same condition
ABCC9 p.Gln852Ter Pathogenic/Likely pathogenic ★★ same condition
ABCC9 p.Gly989Glu Pathogenic/Likely pathogenic ★★ 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/abcc9-p-pro67leu (accessed [today's date]).

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