Is CCDC85A p.Ser536Pro (c.1606T>C) pathogenic?

CCDC85A p.Ser536Pro (c.1606T>C) is classified Uncertain significance in CCDC85A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-20). AlphaMissense: ambiguous (0.4885); Ultra-rare (popmax 0.0165%, mid).

How common is CCDC85A p.Ser536Pro (c.1606T>C) in the general population?

CCDC85A p.Ser536Pro (c.1606T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CCDC85A p.Ser536Pro (c.1606T>C)?

AlphaMissense predicts ambiguous (score 0.4885) — an in-silico prediction, not a clinical call.

CCDC85A p.Ser536Pro

c.1606T>C · VCV3828835

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4885 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Computational evidence

Protein change
AlphaMissense	0.4885	ambiguous
REVEL	0.505	indeterminate
SaProt	LLR -6.77	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 2.1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 200 kb · p 0.0042 · regional, not allelic
Overall
CADD	25.3	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 0.0165% Middle Eastern · 1/6,050 alleles

Filtering AF 0.000804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000651%

Overall 0.00105% 17/1,611,470 alleles · ultra-rare exomes 17/1,459,656 · genomes 0/151,814 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,050
European (non-Finnish)	0.00136%	73,639

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: CCDC85A
Protein: p.Ser536Pro
Coding: c.1606T>C
MANE Select: NM_001080433
Type: single nucleotide variant
Location: chr2:56384299 (GRCh38)
Gene constraint: LOEUF 1.058 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.16

Full CCDC85A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC85A p.Ala13Val Uncertain significance ★ ⚠ same type
CCDC85A p.Ala142Ser Uncertain significance ★ ⚠ same type
CCDC85A p.Ala178Val Uncertain significance ★ ⚠ same type
CCDC85A p.Ala201Pro Uncertain significance ★ ⚠ same type
CCDC85A p.Ala201Val Uncertain significance ★ ⚠ same type
CCDC85A p.Ala21Ser Uncertain significance ★ ⚠ same type
CCDC85A p.Ala21Val Uncertain significance ★ ⚠ same type
CCDC85A p.Ala28Asp 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/ccdc85a-p-ser536pro (accessed [today's date]).

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