Is CCDC77 p.Ser44Tyr (c.131C>A) pathogenic?

CCDC77 p.Ser44Tyr (c.131C>A) is classified Uncertain significance in CCDC77 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.1703); Very rare (popmax 0.00686%, nfe).

How common is CCDC77 p.Ser44Tyr (c.131C>A) in the general population?

CCDC77 p.Ser44Tyr (c.131C>A) is very rare (popmax 0.00686%, nfe) (gnomAD).

What do computational predictors say about CCDC77 p.Ser44Tyr (c.131C>A)?

AlphaMissense predicts likely benign (score 0.1703) — an in-silico prediction, not a clinical call.

CCDC77 p.Ser44Tyr

c.131C>A · VCV4221537

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00686%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1703	likely benign
REVEL	0.292	indeterminate
SaProt	LLR -9.70	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 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 33 kb · p 0.78 · regional, not allelic
Overall
CADD	23.7	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 0.00686% European (non-Finnish) · 81/1,179,978 alleles

Filtering AF 0.00563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00551% 89/1,613,828 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)grpmax	0.00686%	14,568
Admixed American	0.005%	19,986

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: CCDC77
Protein: p.Ser44Tyr
Coding: c.131C>A
MANE Select: NM_032358
Type: single nucleotide variant
Location: chr12:411839 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.42
Residue 44: the 'disordered' region

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-ser44tyr (accessed [today's date]).

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