Is MAP4 p.Glu441Gln (c.1321G>C) pathogenic?

MAP4 p.Glu441Gln (c.1321G>C) is classified Benign in MAP4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-12-04). AlphaMissense: likely benign (0.1096); Common (popmax 7.22%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with MAP4-related disorder.

What condition is associated with MAP4 p.Glu441Gln (c.1321G>C)?

MAP4 p.Glu441Gln (c.1321G>C) is associated with MAP4-related disorder (ClinVar).

What do computational predictors say about MAP4 p.Glu441Gln (c.1321G>C)?

AlphaMissense predicts likely benign (score 0.1096) — an in-silico prediction, not a clinical call.

MAP4 p.Glu441Gln

Q: How common is MAP4 p.Glu441Gln (c.1321G>C) in the general population?

MAP4 p.Glu441Gln (c.1321G>C) is common (popmax 7.22%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1321G>C · rs2230169 · VCV3055750

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1096 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.22%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MAP4-related disorder

Computational evidence

Protein change
AlphaMissense	0.1096	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -9.11	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 0.55	GERP -1.5
Regional constraint	o/e 0.91	unconstrained · MANE · 123 kb · p 2.5e-05 · regional, not allelic
Overall
CADD	18.41	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 7.22% European (non-Finnish) · 85,232/1,180,026 alleles

Filtering AF 7.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.17%

Overall 6.18% 99,813/1,614,208 alleles · common exomes 93,146/1,461,884 · genomes 6,667/152,324 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	7.22%	14
Middle Eastern	6.94%	14
Remaining individualsnot grpmax-eligible	5.51%	18
Ashkenazi Jewishnot grpmax-eligible	5.12%	20
Amishnot grpmax-eligible	4.39%	23
South Asian	4.37%	23
Finnishnot grpmax-eligible	4.36%	23
Admixed American	2.5%	40
African / African-American	1.16%	86
East Asian	0.0267%	3,740

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: MAP4
Protein: p.Glu441Gln
Coding: c.1321G>C
MANE Select: NM_001385682
dbSNP: rs2230169
Type: single nucleotide variant
Location: chr3:47916506 (GRCh38)
Gene constraint: LOEUF 0.512 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 43.03
Residue 441: a UniProt-annotated variant site (in); the '17 x 14 aa tandem repeats' region

Full MAP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MAP4-related disorder

Similar variants

MAP4 c.292+2409G>A Likely benign same condition
MAP4 c.*100G>A Likely benign same condition
MAP4 c.*44G>A Likely benign same condition
MAP4 p.Ala2123= Likely benign same condition
MAP4 p.Ala2134= Likely benign same condition
MAP4 p.Ala437= Likely benign same condition
MAP4 p.Arg23Gln Benign same condition
MAP4 p.Arg23Trp Likely benign ⚠ 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/map4-p-glu441gln (accessed [today's date]).

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