Is NCAPH p.Asp377= (c.1131T>C) pathogenic?

NCAPH p.Asp377= (c.1131T>C) is classified Benign in NCAPH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-09-05). Common (popmax 64.2%, sas) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly 23, primary, autosomal recessive.

What condition is associated with NCAPH p.Asp377= (c.1131T>C)?

NCAPH p.Asp377= (c.1131T>C) is associated with microcephaly 23, primary, autosomal recessive (ClinVar).

NCAPH p.Asp377=

Q: How common is NCAPH p.Asp377= (c.1131T>C) in the general population?

NCAPH p.Asp377= (c.1131T>C) is common (popmax 64.2%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1131T>C · rs3731935 · VCV1321857

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 64.2%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

microcephaly 23, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.6	GERP -1.8
Overall
CADD	1.364	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 64.2% South Asian · 58,468/91,016 alleles

Filtering AF 63.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 63.6%

Overall 28.6% 462,083/1,613,720 alleles · common exomes 427,959/1,461,686 · genomes 34,124/152,034 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	64.2%	2
Middle Eastern	44.6%	2
Ashkenazi Jewishnot grpmax-eligible	37.2%	3
Remaining individualsnot grpmax-eligible	30.6%	3
European (non-Finnish)	27.7%	4
Admixed American	24.5%	4
East Asian	23.4%	4
Amishnot grpmax-eligible	22.9%	4
Finnishnot grpmax-eligible	20.7%	5
African / African-American	7.58%	13

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: NCAPH
Protein: p.Asp377=
Coding: c.1131T>C
MANE Select: NM_015341
dbSNP: rs3731935
Type: single nucleotide variant
Location: chr2:96354311 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 60.16 · 1 PDB
Residue 377: the 'disordered' region

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

Disease context

microcephaly 23, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NCAPH p.Val539Ala Benign ★★ same condition
NCAPH c.19+1G>C Likely pathogenic ★ same condition
NCAPH p.Ala623Thr Uncertain significance ★ ⚠ same condition
NCAPH p.Met651Thr Uncertain significance ★ ⚠ same condition
NCAPH p.Pro243Leu Pathogenic ⚠ same condition
NCAPH p.Arg451Cys Uncertain significance ★★ ⚠ same type
NCAPH c.1002+9A>G Benign/Likely benign ★★ same type
NCAPH p.Arg221Gly Benign ★★ 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/ncaph-p-asp377 (accessed [today's date]).

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