Is ODF2 p.Ser456Arg (c.1368C>A) pathogenic?

ODF2 p.Ser456Arg (c.1368C>A) is classified Uncertain significance in ODF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.7585); Ultra-rare (popmax 0.0414%, nfe).

How common is ODF2 p.Ser456Arg (c.1368C>A) in the general population?

ODF2 p.Ser456Arg (c.1368C>A) is ultra-rare (popmax 0.0414%, nfe) (gnomAD).

What do computational predictors say about ODF2 p.Ser456Arg (c.1368C>A)?

AlphaMissense predicts likely pathogenic (score 0.7585) — an in-silico prediction, not a clinical call.

ODF2 p.Ser456Arg

c.1368C>A · rs148664412 · VCV2589099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7585 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0414%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7585	likely pathogenic
REVEL	0.186	benign-leaning
SaProt	LLR -7.62	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 -1.1	GERP -4, phastCons 0.003
Overall
CADD	13.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S373R vs ClinVar S456R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0414% European (non-Finnish) · 479/1,158,262 alleles

Filtering AF 0.0383% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0371%

Overall 0.0321% 504/1,571,428 alleles · ultra-rare exomes 477/1,419,342 · genomes 27/152,086 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0414%	2,418
Remaining individualsnot grpmax-eligible	0.0311%	3,212
African / African-American	0.00406%	24,651
Finnishnot grpmax-eligible	0.00325%	30,740
Admixed American	0.0019%	52,630

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: ODF2
Protein: p.Ser456Arg
Coding: c.1368C>A
MANE Select: NM_001351578
dbSNP: rs148664412
Type: single nucleotide variant
Location: chr9:128484715 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.64

Full ODF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ODF2 p.Thr793Ser Benign ★★ same type
ODF2 p.Arg263Lys Likely pathogenic ★ ⚠ same type
ODF2 p.Ala120Val Uncertain significance ★ same type
ODF2 p.Ala216Val Uncertain significance ★ ⚠ same type
ODF2 p.Ala297Val Uncertain significance ★ ⚠ same type
ODF2 p.Ala302Val Uncertain significance ★ ⚠ same type
ODF2 p.Ala310Thr Uncertain significance ★ ⚠ same type
ODF2 p.Ala441Ser 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/odf2-p-ser456arg (accessed [today's date]).

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