Is MECOM p.Phe153Leu (c.459C>A) pathogenic?

MECOM p.Phe153Leu (c.459C>A) is classified Likely benign in MECOM (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-16). AlphaMissense: likely pathogenic (0.9414); Ultra-rare (popmax 0.0505%, nfe).

How common is MECOM p.Phe153Leu (c.459C>A) in the general population?

MECOM p.Phe153Leu (c.459C>A) is ultra-rare (popmax 0.0505%, nfe) (gnomAD).

What do computational predictors say about MECOM p.Phe153Leu (c.459C>A)?

AlphaMissense predicts likely pathogenic (score 0.9414) — an in-silico prediction, not a clinical call.

MECOM p.Phe153Leu

c.459C>A · rs199656825 · VCV3049181

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9414 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0505%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9414	likely pathogenic
REVEL	0.218	benign-leaning
SaProt	LLR -6.60	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.75	GERP -3.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 542 kb · p 0.0043 · regional, not allelic
Overall
CADD	20.4	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 0.0505% European (non-Finnish) · 595/1,178,686 alleles

Filtering AF 0.0471% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0457%

Overall 0.0521% 840/1,611,232 alleles · ultra-rare exomes 727/1,458,996 · genomes 113/152,236 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.305%	328
Ashkenazi Jewishnot grpmax-eligible	0.0541%	1,848
European (non-Finnish)grpmax	0.0505%	1,981
Remaining individualsnot grpmax-eligible	0.0337%	2,969
Admixed American	0.0218%	4,586

Finnish 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: MECOM
Protein: p.Phe153Leu
Coding: c.459C>A
MANE Select: NM_004991
dbSNP: rs199656825
Type: single nucleotide variant
Location: chr3:169143749 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 51.04 · 1 PDB
Residue 153: the set domain

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

Similar variants

MECOM p.Phe153= Likely benign ★★ same residue
MECOM p.Arg938Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
MECOM p.Arg938Trp Pathogenic/Likely pathogenic ★★ same type
MECOM p.Thr944Ile Likely pathogenic ★★ same type
MECOM c.2577+4A>T Uncertain significance ★★ same type
MECOM c.3585+3A>G Uncertain significance ★★ same type
MECOM p.Ala1022Gly Uncertain significance ★★ ⚠ same type
MECOM p.Ala1146Ser 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/mecom-p-phe153leu (accessed [today's date]).

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