Is MCPH1 p.Asp115Val (c.344A>T) pathogenic?

MCPH1 p.Asp115Val (c.344A>T) is classified Uncertain significance in MCPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-25). AlphaMissense: likely benign (0.3288); Ultra-rare (popmax 0.012%, afr); Associated with Inborn genetic diseases.

What condition is associated with MCPH1 p.Asp115Val (c.344A>T)?

MCPH1 p.Asp115Val (c.344A>T) is associated with Inborn genetic diseases (ClinVar).

How common is MCPH1 p.Asp115Val (c.344A>T) in the general population?

MCPH1 p.Asp115Val (c.344A>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about MCPH1 p.Asp115Val (c.344A>T)?

AlphaMissense predicts likely benign (score 0.3288) — an in-silico prediction, not a clinical call.

MCPH1 p.Asp115Val

c.344A>T · rs562954265 · VCV2392025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3288 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3288	likely benign
REVEL	0.235	benign-leaning
SaProt	LLR -11.44	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	26.5	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 0.012% African / African-American · 9/75,042 alleles

Filtering AF 0.00622% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000806% 13/1,613,848 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,338
Admixed American	0.005%	20,001
European (non-Finnish)	8.48e-05%	1,179,862

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.Asp115Val
Coding: c.344A>T
MANE Select: NM_024596
dbSNP: rs562954265
Type: single nucleotide variant
Location: chr8:6436070 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MCPH1 p.Asp115Tyr Uncertain significance ★ ⚠ same residue
MCPH1 c.1935+6T>C Uncertain significance ★★ same condition
MCPH1 p.Ala401Val Uncertain significance ★★ ⚠ same condition
MCPH1 p.Ala404Val Uncertain significance ★★ ⚠ same condition
MCPH1 p.Arg373Thr Uncertain significance ★★ ⚠ same condition
MCPH1 p.Arg379Ile Uncertain significance ★★ ⚠ same condition
MCPH1 p.Arg703His Uncertain significance ★★ ⚠ same condition
MCPH1 p.Arg785Trp Uncertain significance ★★ ⚠ 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/mcph1-p-asp115val (accessed [today's date]).

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