Is FECH p.Pro307Leu (c.920C>T) pathogenic?

FECH p.Pro307Leu (c.920C>T) is classified Uncertain significance in FECH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: ambiguous (0.4001); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with FECH p.Pro307Leu (c.920C>T)?

FECH p.Pro307Leu (c.920C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FECH p.Pro307Leu (c.920C>T) in the general population?

FECH p.Pro307Leu (c.920C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about FECH p.Pro307Leu (c.920C>T)?

AlphaMissense predicts ambiguous (score 0.4001) — an in-silico prediction, not a clinical call.

FECH p.Pro307Leu

c.920C>T · VCV3514587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4001 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4001	ambiguous
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -10.64	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 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 36 kb · p 2e-05 · regional, not allelic
Overall
CADD	27.5	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 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00143% 23/1,614,020 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,927
East Asiangrpmax	0.00446%	22,442
European (non-Finnish)	0.00119%	84,286

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: FECH
Protein: p.Pro307Leu
Coding: c.920C>T
MANE Select: NM_000140
Type: single nucleotide variant
Location: chr18:57554417 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB
Residue 307: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FECH p.Pro307= Benign ★★ same residue
FECH p.Leu4Phe Uncertain significance ★★ ⚠ same condition
FECH p.Lys320Arg Uncertain significance ★★ ⚠ same condition
FECH p.Met267Thr Uncertain significance ★★ ⚠ same condition
FECH p.Ser197Thr Uncertain significance ★★ ⚠ same condition
FECH p.Ser268Phe Uncertain significance ★★ ⚠ same condition
FECH p.Val166Ile Uncertain significance ★★ ⚠ same condition
FECH p.Asn105= Likely benign ★★ 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/fech-p-pro307leu (accessed [today's date]).

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