Is FECH p.Glu317Lys (c.949G>A) pathogenic?

FECH p.Glu317Lys (c.949G>A) is classified Benign in FECH (ClinVar, Single submitter, 2 submitters; last evaluated 2025-02-19). AlphaMissense: likely benign (0.1128); Rare (popmax 0.559%, sas).

How common is FECH p.Glu317Lys (c.949G>A) in the general population?

FECH p.Glu317Lys (c.949G>A) is rare (popmax 0.559%, sas) (gnomAD).

What do computational predictors say about FECH p.Glu317Lys (c.949G>A)?

AlphaMissense predicts likely benign (score 0.1128) — an in-silico prediction, not a clinical call.

FECH p.Glu317Lys

c.949G>A · rs200280268 · VCV2910597

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1128 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.559%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1128	likely benign
REVEL	0.665	pathogenic-leaning
SaProt	LLR -8.75	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.86	GERP -0.083, phastCons 0.28
Regional constraint	o/e 0.81	unconstrained · MANE · 36 kb · p 2e-05 · regional, not allelic
Overall
CADD	22.1	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 0.559% South Asian · 509/91,076 alleles

Filtering AF 0.519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.503%

Overall 0.033% 532/1,614,186 alleles · rare exomes 505/1,461,866 · genomes 27/152,320 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.559%	179
Remaining individualsnot grpmax-eligible	0.0192%	5,209
East Asian	0.0178%	5,610
Admixed American	0.00167%	60,030
African / African-American	0.00133%	75,052
European (non-Finnish)	8.47e-05%	1,180,018

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.Glu317Lys
Coding: c.949G>A
MANE Select: NM_000140
dbSNP: rs200280268
Type: single nucleotide variant
Location: chr18:57554388 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB
Residue 317: an α-helix

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

Similar variants

FECH p.Glu317Asp Uncertain significance ★ ⚠ same residue
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

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-glu317lys (accessed [today's date]).

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