Is MECOM p.Pro120Ser (c.358C>T) pathogenic?

MECOM p.Pro120Ser (c.358C>T) is classified Benign/Likely benign in MECOM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-26). AlphaMissense: likely benign (0.0823); Common (popmax 29.3%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about MECOM p.Pro120Ser (c.358C>T)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

MECOM p.Pro120Ser

Q: How common is MECOM p.Pro120Ser (c.358C>T) in the general population?

MECOM p.Pro120Ser (c.358C>T) is common (popmax 29.3%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.358C>T · VCV4684739

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 29.3%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -5.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 0.13, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 542 kb · p 0.0043 · regional, not allelic
Overall
CADD	19.54	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 29.3% Admixed American · 17,495/59,756 alleles

Filtering AF 28.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 28.8%

Overall 12% 193,218/1,605,386 alleles · common exomes 173,476/1,453,304 · genomes 19,742/152,082 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	29.3%	3
East Asian	15%	7
African / African-American	12.8%	8
European (non-Finnish)	11.7%	9
Remaining individualsnot grpmax-eligible	11.5%	9
Finnishnot grpmax-eligible	10.3%	10
Amishnot grpmax-eligible	8.66%	12
South Asian	7.07%	14
Ashkenazi Jewishnot grpmax-eligible	5.67%	18
Middle Eastern	5.45%	18

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.Pro120Ser
Coding: c.358C>T
MANE Select: NM_004991
Type: single nucleotide variant
Location: chr3:169381204 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 51.04 · 1 PDB
Residue 120: the set domain; a UniProt-annotated variant site (in)

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

Similar variants

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
MECOM p.Ala1228Val 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-pro120ser (accessed [today's date]).

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