Is CCDC77 p.Leu481Val (c.1441C>G) pathogenic?

CCDC77 p.Leu481Val (c.1441C>G) is classified Uncertain significance in CCDC77 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-30). AlphaMissense: likely benign (0.1449); Very rare (popmax 0.000508%, nfe).

How common is CCDC77 p.Leu481Val (c.1441C>G) in the general population?

CCDC77 p.Leu481Val (c.1441C>G) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about CCDC77 p.Leu481Val (c.1441C>G)?

AlphaMissense predicts likely benign (score 0.1449) — an in-silico prediction, not a clinical call.

CCDC77 p.Leu481Val

c.1441C>G · rs139150349 · VCV2262705

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1449 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1449	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -9.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.4	GERP -0.28, phastCons 0.97
Regional constraint	o/e 0.99	unconstrained · MANE · 33 kb · p 0.78 · regional, not allelic
Overall
CADD	21.8	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 0.000508% European (non-Finnish) · 6/1,180,008 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,884 alleles · very rare

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: CCDC77
Protein: p.Leu481Val
Coding: c.1441C>G
MANE Select: NM_032358
dbSNP: rs139150349
Type: single nucleotide variant
Location: chr12:441894 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.42

Full CCDC77 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC77 p.Ala157Pro Uncertain significance ★ ⚠ same type
CCDC77 p.Ala194Gly Uncertain significance ★ ⚠ same type
CCDC77 p.Ala445Pro Uncertain significance ★ ⚠ same type
CCDC77 p.Arg134Leu Uncertain significance ★ ⚠ same type
CCDC77 p.Arg216Gly Uncertain significance ★ ⚠ same type
CCDC77 p.Arg251Gln Uncertain significance ★ ⚠ same type
CCDC77 p.Arg251Leu Uncertain significance ★ ⚠ same type
CCDC77 p.Arg251Trp 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/ccdc77-p-leu481val (accessed [today's date]).

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