Is CCNC p.Thr186Met (c.557C>T) pathogenic?

CCNC p.Thr186Met (c.557C>T) is classified Uncertain significance in CCNC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: ambiguous (0.5189); Very rare (popmax 0.00179%, nfe).

How common is CCNC p.Thr186Met (c.557C>T) in the general population?

CCNC p.Thr186Met (c.557C>T) is very rare (popmax 0.00179%, nfe) (gnomAD).

What do computational predictors say about CCNC p.Thr186Met (c.557C>T)?

AlphaMissense predicts ambiguous (score 0.5189) — an in-silico prediction, not a clinical call.

CCNC p.Thr186Met

c.557C>T · VCV3997603

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5189 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00179%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5189	ambiguous
REVEL	0.654	pathogenic-leaning
SaProt	LLR -10.40	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 25 kb · p 2.1e-12 · regional, not allelic
Overall
CADD	29.8	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 0.00179% European (non-Finnish) · 21/1,171,416 alleles

Filtering AF 0.00115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000978%

Overall 0.00143% 23/1,603,880 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00322%	31,056
European (non-Finnish)grpmax	0.00179%	55,782

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: CCNC
Protein: p.Thr186Met
Coding: c.557C>T
MANE Select: NM_005190
Type: single nucleotide variant
Location: chr6:99549549 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI 0.75 (gnomAD)
Structure: AlphaFold pLDDT 92.05 · 36 PDB
Residue 186: a turn

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

Similar variants

CCNC p.Arg25Cys Uncertain significance ★ ⚠ same type
CCNC p.Arg25His Uncertain significance ★ ⚠ same type
CCNC p.Asp223Gly Uncertain significance ★ ⚠ same type
CCNC p.Gln209His Uncertain significance ★ ⚠ same type
CCNC p.Glu36Ter Uncertain significance ★ same type
CCNC p.Ile15Ser Uncertain significance ★ ⚠ same type
CCNC p.Lys256Arg Uncertain significance ★ ⚠ same type
CCNC p.Lys256Gln 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/ccnc-p-thr186met (accessed [today's date]).

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