Is CCDC73 p.Ile416Phe (c.1246A>T) pathogenic?

CCDC73 p.Ile416Phe (c.1246A>T) is classified Uncertain significance in CCDC73 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0951); Ultra-rare (popmax 0.0267%, nfe).

How common is CCDC73 p.Ile416Phe (c.1246A>T) in the general population?

CCDC73 p.Ile416Phe (c.1246A>T) is ultra-rare (popmax 0.0267%, nfe) (gnomAD).

What do computational predictors say about CCDC73 p.Ile416Phe (c.1246A>T)?

AlphaMissense predicts likely benign (score 0.0951) — an in-silico prediction, not a clinical call.

CCDC73 p.Ile416Phe

c.1246A>T · rs191760480 · VCV3139348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0951 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0951	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -6.37	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 -0.057	GERP -3.9
Regional constraint	o/e 0.88	unconstrained · MANE · 157 kb · p 5.1e-05 · regional, not allelic
Overall
CADD	0.204	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 0.0267% European (non-Finnish) · 313/1,172,572 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0232%

Overall 0.0206% 328/1,591,486 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0267%	3,746
African / African-American	0.0122%	8,167
Remaining individualsnot grpmax-eligible	0.00812%	12,310
Admixed American	0.00184%	54,336

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: CCDC73
Protein: p.Ile416Phe
Coding: c.1246A>T
MANE Select: NM_001008391
dbSNP: rs191760480
Type: single nucleotide variant
Location: chr11:32616069 (GRCh38)
Gene constraint: LOEUF 1.103 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.16

Full CCDC73 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC73 p.Ile416Val Likely benign ★ same residue
CCDC73 p.Ala220Glu Uncertain significance ★ ⚠ same type
CCDC73 p.Ala221Val Uncertain significance ★ ⚠ same type
CCDC73 p.Ala614Val Uncertain significance ★ ⚠ same type
CCDC73 p.Ala717Val Uncertain significance ★ ⚠ same type
CCDC73 p.Ala789Thr Uncertain significance ★ ⚠ same type
CCDC73 p.Ala88Thr Uncertain significance ★ ⚠ same type
CCDC73 p.Ala974Asp 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/ccdc73-p-ile416phe (accessed [today's date]).

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