Is CCDC91 p.Arg257Ser (c.771G>C) pathogenic?

CCDC91 p.Arg257Ser (c.771G>C) is classified Uncertain significance in CCDC91 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: likely pathogenic (0.7964); Very rare (popmax 0.00248%, nfe).

How common is CCDC91 p.Arg257Ser (c.771G>C) in the general population?

CCDC91 p.Arg257Ser (c.771G>C) is very rare (popmax 0.00248%, nfe) (gnomAD).

What do computational predictors say about CCDC91 p.Arg257Ser (c.771G>C)?

AlphaMissense predicts likely pathogenic (score 0.7964) — an in-silico prediction, not a clinical call.

CCDC91 p.Arg257Ser

c.771G>C · rs1949729725 · VCV3139633

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00248%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7964	likely pathogenic
REVEL	0.215	benign-leaning
SaProt	LLR -5.88	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 292 kb · p 0.81 · regional, not allelic
Overall
CADD	21.7	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 0.00248% European (non-Finnish) · 29/1,170,202 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0015%

Overall 0.00201% 29/1,444,786 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: CCDC91
Protein: p.Arg257Ser
Coding: c.771G>C
MANE Select: NM_018318
dbSNP: rs1949729725
Type: single nucleotide variant
Location: chr12:28450169 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 76.04 · 1 PDB
Residue 257: the 'homodimerization' region

Full CCDC91 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC91 p.Asp121Gly Benign ★★ same type
CCDC91 p.Gln403Lys Benign ★★ ⚠ same type
CCDC91 p.Ala127Thr Uncertain significance ★ ⚠ same type
CCDC91 p.Ala181Thr Uncertain significance ★ ⚠ same type
CCDC91 p.Ala209Thr Uncertain significance ★ ⚠ same type
CCDC91 p.Ala219Thr Uncertain significance ★ ⚠ same type
CCDC91 p.Ala28Ser Uncertain significance ★ ⚠ same type
CCDC91 p.Ala334Gly 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/ccdc91-p-arg257ser (accessed [today's date]).

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