Is FECH p.Pro404Leu (c.1211C>T) pathogenic?

FECH p.Pro404Leu (c.1211C>T) is classified Uncertain significance in FECH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-20). AlphaMissense: ambiguous (0.4532); Very rare (popmax 0.00891%, eas).

How common is FECH p.Pro404Leu (c.1211C>T) in the general population?

FECH p.Pro404Leu (c.1211C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about FECH p.Pro404Leu (c.1211C>T)?

AlphaMissense predicts ambiguous (score 0.4532) — an in-silico prediction, not a clinical call.

FECH p.Pro404Leu

c.1211C>T · VCV4542265

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4532 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4532	ambiguous
REVEL	0.854	moderately pathogenic-leaning
SaProt	LLR -8.40	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
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	29.4	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 0.00891% East Asian · 4/44,894 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00353% 57/1,614,004 alleles · very rare exomes 55/1,461,830 · genomes 2/152,174 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,223
European (non-Finnish)	0.00424%	23,600
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
South Asian	0.0022%	45,543

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.Pro404Leu
Coding: c.1211C>T
MANE Select: NM_000140
Type: single nucleotide variant
Location: chr18:57550773 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB

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

Similar variants

FECH c.1137+3A>G Pathogenic/Likely pathogenic ★★ same type
FECH c.314+2T>G Pathogenic/Likely pathogenic ★★ same type
FECH c.463+1G>C Pathogenic ★★ same type
FECH c.598+1G>T Pathogenic ★★ same type
FECH c.599-2A>G Pathogenic ★★ same type
FECH c.913-2A>G Likely pathogenic ★★ same type
FECH p.Arg115Ter Pathogenic/Likely pathogenic ★★ same type
FECH p.Arg298Ter 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/fech-p-pro404leu (accessed [today's date]).

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