Is FECH p.Ser268Phe (c.803C>T) pathogenic?

FECH p.Ser268Phe (c.803C>T) is classified Uncertain significance in FECH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-29). AlphaMissense: ambiguous (0.3486); Very rare (popmax 0.000771%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FECH p.Ser268Phe (c.803C>T)?

FECH p.Ser268Phe (c.803C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FECH p.Ser268Phe (c.803C>T) in the general population?

FECH p.Ser268Phe (c.803C>T) is very rare (popmax 0.000771%, nfe) (gnomAD).

What do computational predictors say about FECH p.Ser268Phe (c.803C>T)?

AlphaMissense predicts ambiguous (score 0.3486) — an in-silico prediction, not a clinical call.

FECH p.Ser268Phe

c.803C>T · rs2050907331 · VCV2800260

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3486 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000771%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3486	ambiguous
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -13.12	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.59 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 36 kb · p 2e-05 · regional, not allelic
Overall
CADD	34.0	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 0.000771% European (non-Finnish) · 9/1,167,808 alleles

Filtering AF 0.000363% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000263%

Overall 0.000562% 9/1,600,228 alleles · very rare exomes 9/1,448,024 · genomes 0/152,204 · 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: FECH
Protein: p.Ser268Phe
Coding: c.803C>T
MANE Select: NM_000140
dbSNP: rs2050907331
Type: single nucleotide variant
Location: chr18:57559146 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB
Residue 268: an α-helix

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.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.Val166Ile Uncertain significance ★★ ⚠ same condition
FECH p.Asn105= Likely benign ★★ same condition
FECH p.Ala10Thr Uncertain significance ★ same condition
FECH p.Arg13Ser 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/fech-p-ser268phe (accessed [today's date]).

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