Is OFD1 p.Phe818Leu (c.2452T>C) pathogenic?

OFD1 p.Phe818Leu (c.2452T>C) is classified Likely benign in OFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-01). AlphaMissense: ambiguous (0.434); Very rare (popmax 0.000227%, nfe).

How common is OFD1 p.Phe818Leu (c.2452T>C) in the general population?

OFD1 p.Phe818Leu (c.2452T>C) is very rare (popmax 0.000227%, nfe) (gnomAD).

What do computational predictors say about OFD1 p.Phe818Leu (c.2452T>C)?

AlphaMissense predicts ambiguous (score 0.434) — an in-silico prediction, not a clinical call.

OFD1 p.Phe818Leu

c.2452T>C · VCV4083699

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.434 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000227%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.434	ambiguous · top 10% in OFD1
REVEL	0.137	moderately benign-leaning
SaProt	LLR -5.22	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.061	GERP 2.5, phastCons 0.001
Regional constraint	o/e 1.02	unconstrained · MANE · 8,639 bp · p 0.77 · regional, not allelic
Overall
CADD	4.567	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 0.000227% European (non-Finnish) · 2/881,711 alleles

Filtering AF 3.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000167% 2/1,196,711 alleles · very rare exomes 2/1,082,689 · genomes 0/114,022 · joint denominator

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: OFD1
Protein: p.Phe818Leu
Coding: c.2452T>C
MANE Select: NM_003611
Type: single nucleotide variant
Location: chrX:13762408 (GRCh38)
Structure: AlphaFold pLDDT 68.41
Residue 818: the 'mediates the interaction with sdccag8' region

Full OFD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

OFD1 c.1411+1G>A Pathogenic ★★ same type
OFD1 c.2600-1G>C Pathogenic/Likely pathogenic ★★ same type
OFD1 c.655-8A>G Likely pathogenic ★★ same type
OFD1 p.Arg367Ter Pathogenic ★★ same type
OFD1 p.Arg41Ter Pathogenic ★★ same type
OFD1 p.Arg890Ter Pathogenic/Likely pathogenic ★★ same type
OFD1 p.Arg909Ter Pathogenic/Likely pathogenic ★★ same type
OFD1 p.Gln966Ter Pathogenic/Likely pathogenic ★★ 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/ofd1-p-phe818leu (accessed [today's date]).

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