Is CCDC66 p.Ile53Phe (c.157A>T) pathogenic?

CCDC66 p.Ile53Phe (c.157A>T) is classified Uncertain significance in CCDC66 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.0901); Rare (popmax 0.117%, mid).

How common is CCDC66 p.Ile53Phe (c.157A>T) in the general population?

CCDC66 p.Ile53Phe (c.157A>T) is rare (popmax 0.117%, mid) (gnomAD).

What do computational predictors say about CCDC66 p.Ile53Phe (c.157A>T)?

AlphaMissense predicts likely benign (score 0.0901) — an in-silico prediction, not a clinical call.

CCDC66 p.Ile53Phe

c.157A>T · rs186629692 · VCV2367339

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0901 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.117%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0901	likely benign
REVEL	0.394	indeterminate
SaProt	LLR -6.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -3.5, phastCons 0.03
Regional constraint	o/e 1.05	unconstrained · MANE · 64 kb · p 0.12 · regional, not allelic
Overall
CADD	16.72	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 0.117% Middle Eastern · 7/5,988 alleles

Filtering AF 0.0548% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0389%

Overall 0.00322% 50/1,551,660 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.117%	855
African / African-American	0.0396%	2,522
Remaining individualsnot grpmax-eligible	0.0216%	4,629
South Asian	0.00119%	84,020

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: CCDC66
Protein: p.Ile53Phe
Coding: c.157A>T
MANE Select: NM_001141947
dbSNP: rs186629692
Type: single nucleotide variant
Location: chr3:56563738 (GRCh38)
Gene constraint: LOEUF 1.135 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.56

Full CCDC66 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC66 p.Ile53Val Uncertain significance ★ ⚠ same residue
CCDC66 p.Ala114Val Uncertain significance ★ ⚠ same type
CCDC66 p.Ala142Gly Uncertain significance ★ ⚠ same type
CCDC66 p.Ala323Thr Uncertain significance ★ ⚠ same type
CCDC66 p.Ala668Pro Uncertain significance ★ ⚠ same type
CCDC66 p.Ala937Val Uncertain significance ★ ⚠ same type
CCDC66 p.Arg122Ser Uncertain significance ★ ⚠ same type
CCDC66 p.Arg443Cys 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/ccdc66-p-ile53phe (accessed [today's date]).

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