Is ADHFE1 p.Pro180Leu (c.539C>T) pathogenic?

ADHFE1 p.Pro180Leu (c.539C>T) is classified Uncertain significance in ADHFE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-20). AlphaMissense: likely benign (0.3132); Very rare (popmax 6.87e-05%).

How common is ADHFE1 p.Pro180Leu (c.539C>T) in the general population?

ADHFE1 p.Pro180Leu (c.539C>T) is very rare (popmax 6.87e-05%) (gnomAD).

What do computational predictors say about ADHFE1 p.Pro180Leu (c.539C>T)?

AlphaMissense predicts likely benign (score 0.3132) — an in-silico prediction, not a clinical call.

ADHFE1 p.Pro180Leu

c.539C>T · rs2487664736 · VCV2232665

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3132 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.87e-05%)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3132	likely benign
REVEL	0.675	pathogenic-leaning
SaProt	LLR -11.94	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 36 kb · p 0.69 · regional, not allelic
Overall
CADD	28.6	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 6.87e-05%

Overall 6.87e-05% 1/1,455,930 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: ADHFE1
Protein: p.Pro180Leu
Coding: c.539C>T
MANE Select: NM_144650
dbSNP: rs2487664736
Type: single nucleotide variant
Location: chr8:66445403 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.00

Full ADHFE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADHFE1 p.Ala136Asp Uncertain significance ★ ⚠ same type
ADHFE1 p.Ala233Thr Uncertain significance ★ ⚠ same type
ADHFE1 p.Ala237Thr Uncertain significance ★ ⚠ same type
ADHFE1 p.Ala247Ser Uncertain significance ★ ⚠ same type
ADHFE1 p.Ala271Glu Uncertain significance ★ ⚠ same type
ADHFE1 p.Ala283Ser Uncertain significance ★ ⚠ same type
ADHFE1 p.Ala283Val Uncertain significance ★ ⚠ same type
ADHFE1 p.Ala286Glu 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/adhfe1-p-pro180leu (accessed [today's date]).

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