Is NCAPD2 p.Ile640= (c.1920C>A) pathogenic?

NCAPD2 p.Ile640= (c.1920C>A) is classified Benign in NCAPD2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-27). Common (popmax 59.3%, amr) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly 21, primary, autosomal recessive.

What condition is associated with NCAPD2 p.Ile640= (c.1920C>A)?

NCAPD2 p.Ile640= (c.1920C>A) is associated with microcephaly 21, primary, autosomal recessive (ClinVar).

NCAPD2 p.Ile640=

Q: How common is NCAPD2 p.Ile640= (c.1920C>A) in the general population?

NCAPD2 p.Ile640= (c.1920C>A) is common (popmax 59.3%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1920C>A · rs917634 · VCV1238523

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 59.3%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

microcephaly 21, 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 1.1	GERP 0.6, phastCons 1
Overall
CADD	7.998	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 59.3% Admixed American · 35,580/60,020 alleles

Filtering AF 58.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 58.6%

Overall 46.3% 747,596/1,613,514 alleles · common exomes 671,004/1,461,476 · genomes 76,592/152,038 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	59.3%	2
African / African-American	59.1%	2
East Asian	52.3%	2
Ashkenazi Jewishnot grpmax-eligible	50.7%	2
Remaining individualsnot grpmax-eligible	47.8%	2
Middle Eastern	47.8%	2
Amishnot grpmax-eligible	45.5%	2
European (non-Finnish)	45.2%	2
Finnishnot grpmax-eligible	45.1%	2
South Asian	37.6%	3

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: NCAPD2
Protein: p.Ile640=
Coding: c.1920C>A
MANE Select: NM_014865
dbSNP: rs917634
Type: single nucleotide variant
Location: chr12:6522003 (GRCh38)
Gene constraint: LOEUF 0.687 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.94

Full NCAPD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly 21, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NCAPD2 p.Asn509Ser Uncertain significance ★★ ⚠ same condition
NCAPD2 p.Gln670Ter Uncertain significance ★★ same condition
NCAPD2 c.127+27C>T Benign ★★ same condition
NCAPD2 c.2566+30A>T Benign ★★ same condition
NCAPD2 c.3573-13C>T Benign ★★ same condition
NCAPD2 p.Arg1100= Benign ★★ same condition
NCAPD2 p.Asn1161= Benign ★★ same condition
NCAPD2 p.Gln83Glu 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/ncapd2-p-ile640 (accessed [today's date]).

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