Is IFT80 p.Leu680Phe (c.2038C>T) pathogenic?

IFT80 p.Leu680Phe (c.2038C>T) is classified Uncertain significance in IFT80 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-15). AlphaMissense: ambiguous (0.3496); Very rare (popmax 0.00017%, nfe); Associated with asphyxiating thoracic dystrophy 2.

What condition is associated with IFT80 p.Leu680Phe (c.2038C>T)?

IFT80 p.Leu680Phe (c.2038C>T) is associated with asphyxiating thoracic dystrophy 2 (ClinVar).

How common is IFT80 p.Leu680Phe (c.2038C>T) in the general population?

IFT80 p.Leu680Phe (c.2038C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about IFT80 p.Leu680Phe (c.2038C>T)?

AlphaMissense predicts ambiguous (score 0.3496) — an in-silico prediction, not a clinical call.

IFT80 p.Leu680Phe

c.2038C>T · rs747952085 · VCV901493

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3496 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

asphyxiating thoracic dystrophy 2

Computational evidence

Protein change
AlphaMissense	0.3496	ambiguous
REVEL	0.753	pathogenic-leaning
SaProt	LLR -11.37	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 126 kb · p 0.00011 · regional, not allelic
Overall
CADD	28.1	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 0.00017% European (non-Finnish) · 2/1,179,690 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,586 alleles · very rare exomes 2/1,461,296 · genomes 0/152,290 · 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: IFT80
Protein: p.Leu680Phe
Coding: c.2038C>T
MANE Select: NM_020800
dbSNP: rs747952085
Type: single nucleotide variant
Location: chr3:160277367 (GRCh38)
Gene constraint: LOEUF 0.739 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.50

Full IFT80 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

asphyxiating thoracic dystrophy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IFT80 p.Leu680Pro Uncertain significance ⚠ same residue
IFT80 p.Arg495Ter Pathogenic/Likely pathogenic ★★ same condition
IFT80 c.1076+6C>A Uncertain significance ★★ same condition
IFT80 c.1836+5T>C Uncertain significance ★★ same condition
IFT80 c.370+6T>C Uncertain significance ★★ same condition
IFT80 c.*108A>G Uncertain significance ★★ same condition
IFT80 p.Ala236Val Uncertain significance ★★ ⚠ same condition
IFT80 p.Arg220Cys Uncertain significance ★★ ⚠ same condition

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/ift80-p-leu680phe (accessed [today's date]).

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