Is MCPH1 p.Ile481Phe (c.1441A>T) pathogenic?

MCPH1 p.Ile481Phe (c.1441A>T) is classified Conflicting classifications of pathogenicity in MCPH1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-28). AlphaMissense: likely benign (0.086); Ultra-rare (popmax 0.0165%, mid).

How common is MCPH1 p.Ile481Phe (c.1441A>T) in the general population?

MCPH1 p.Ile481Phe (c.1441A>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MCPH1 p.Ile481Phe (c.1441A>T)?

AlphaMissense predicts likely benign (score 0.086) — an in-silico prediction, not a clinical call.

MCPH1 p.Ile481Phe

c.1441A>T · rs768776312 · VCV493466

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.086 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.086	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -5.89	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 -0.33	GERP -3.3
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	3.927	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000479% 7/1,461,876 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.000508%	196,671

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: MCPH1
Protein: p.Ile481Phe
Coding: c.1441A>T
MANE Select: NM_024596
dbSNP: rs768776312
Type: single nucleotide variant
Location: chr8:6445163 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB

Full MCPH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MCPH1 p.Ile481= Conflicting classifications of pathogenicity ★ same residue
MCPH1 p.Ile481Leu Uncertain significance ★ ⚠ same residue
MCPH1 p.Ile481Thr Uncertain significance ★ ⚠ same residue
MCPH1 p.Ile481Val Uncertain significance ★ ⚠ same residue
MCPH1 c.321+2T>C Likely pathogenic ★★ same type
MCPH1 c.322-1G>C Pathogenic/Likely pathogenic ★★ same type
MCPH1 p.Gln199Ter Pathogenic ★★ same type
MCPH1 p.Gln386Ter 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/mcph1-p-ile481phe (accessed [today's date]).

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