Is ACAN p.Pro185Thr (c.553C>A) pathogenic?

ACAN p.Pro185Thr (c.553C>A) is classified Conflicting classifications of pathogenicity in ACAN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-03). AlphaMissense: likely pathogenic (0.6826); Rare (popmax 0.177%, eas).

How common is ACAN p.Pro185Thr (c.553C>A) in the general population?

ACAN p.Pro185Thr (c.553C>A) is rare (popmax 0.177%, eas) (gnomAD).

What do computational predictors say about ACAN p.Pro185Thr (c.553C>A)?

AlphaMissense predicts likely pathogenic (score 0.6826) — an in-silico prediction, not a clinical call.

ACAN p.Pro185Thr

c.553C>A · rs751285545 · VCV1343545

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6826 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.177%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6826	likely pathogenic
REVEL	0.326	indeterminate
SaProt	LLR -10.63	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 2.7	GERP -0.31, phastCons 0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	21.3	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 0.177% East Asian · 79/44,622 alleles

Filtering AF 0.146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.134%

Overall 0.00517% 83/1,605,866 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.177%	565
Remaining individualsnot grpmax-eligible	0.00483%	20,716
Admixed American	0.00169%	59,080

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: ACAN
Protein: p.Pro185Thr
Coding: c.553C>A
MANE Select: NM_001369268
dbSNP: rs751285545
Type: single nucleotide variant
Location: chr15:88840110 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 185: a disulfide bond; an α-helix; the link 1 domain; the 'g1-b' region

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

Similar variants

ACAN c.1733-2A>G Likely pathogenic ★★ same type
ACAN c.630-13G>A Pathogenic ★★ same type
ACAN c.7302+1G>A Pathogenic/Likely pathogenic ★★ same type
ACAN p.Arg236Ter Pathogenic ★★ same type
ACAN p.Arg386Ter Pathogenic/Likely pathogenic ★★ same type
ACAN p.Arg394Ter Pathogenic ★★ same type
ACAN p.Arg675Ter Pathogenic/Likely pathogenic ★★ same type
ACAN p.Asp2419Asn Likely pathogenic ★★ 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/acan-p-pro185thr (accessed [today's date]).

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