Is CCDC86 p.Arg249His (c.746G>A) pathogenic?

CCDC86 p.Arg249His (c.746G>A) is classified Uncertain significance in CCDC86 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-17). AlphaMissense: likely benign (0.2678); Ultra-rare (popmax 0.0311%, sas).

How common is CCDC86 p.Arg249His (c.746G>A) in the general population?

CCDC86 p.Arg249His (c.746G>A) is ultra-rare (popmax 0.0311%, sas) (gnomAD).

What do computational predictors say about CCDC86 p.Arg249His (c.746G>A)?

AlphaMissense predicts likely benign (score 0.2678) — an in-silico prediction, not a clinical call.

CCDC86 p.Arg249His

c.746G>A · rs780403526 · VCV3139499

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2678 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0311%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2678	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -7.23	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 6.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,197 bp · p 0.43 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0311% South Asian · 26/83,642 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0186%

Overall 0.00249% 39/1,564,424 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0311%	3,217
African / African-American	0.00137%	73,218
European (non-Finnish)	0.00104%	96,149

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: CCDC86
Protein: p.Arg249His
Coding: c.746G>A
MANE Select: NM_024098
dbSNP: rs780403526
Type: single nucleotide variant
Location: chr11:60842870 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.88 · 10 PDB
Residue 249: the 'disordered' region

Full CCDC86 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC86 p.Ala139Thr Uncertain significance ★ ⚠ same type
CCDC86 p.Ala139Val Uncertain significance ★ ⚠ same type
CCDC86 p.Ala149Gly Uncertain significance ★ ⚠ same type
CCDC86 p.Ala149Thr Uncertain significance ★ ⚠ same type
CCDC86 p.Ala169Gly Uncertain significance ★ ⚠ same type
CCDC86 p.Ala169Pro Uncertain significance ★ ⚠ same type
CCDC86 p.Ala358Pro Uncertain significance ★ ⚠ same type
CCDC86 p.Ala89Thr 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/ccdc86-p-arg249his (accessed [today's date]).

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