Is NCAPD2 p.Phe543Val (c.1627T>G) pathogenic?

NCAPD2 p.Phe543Val (c.1627T>G) is classified Likely benign in NCAPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: ambiguous (0.4539); Rare (popmax 0.192%, afr); Associated with Inborn genetic diseases.

What condition is associated with NCAPD2 p.Phe543Val (c.1627T>G)?

NCAPD2 p.Phe543Val (c.1627T>G) is associated with Inborn genetic diseases (ClinVar).

How common is NCAPD2 p.Phe543Val (c.1627T>G) in the general population?

NCAPD2 p.Phe543Val (c.1627T>G) is rare (popmax 0.192%, afr) (gnomAD).

What do computational predictors say about NCAPD2 p.Phe543Val (c.1627T>G)?

AlphaMissense predicts ambiguous (score 0.4539) — an in-silico prediction, not a clinical call.

NCAPD2 p.Phe543Val

c.1627T>G · VCV3403182

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4539 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.192%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4539	ambiguous
REVEL	0.17	moderately benign-leaning
SaProt	LLR -14.78	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 36 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	25.1	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 0.192% African / African-American · 144/75,066 alleles

Filtering AF 0.166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.157%

Overall 0.00979% 158/1,614,160 alleles · rare exomes 86/1,461,806 · genomes 72/152,354 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.192%	521
Admixed American	0.0133%	7,502
Remaining individualsnot grpmax-eligible	0.008%	12,500
European (non-Finnish)	8.47e-05%	1,179,980

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.Phe543Val
Coding: c.1627T>G
MANE Select: NM_014865
Type: single nucleotide variant
Location: chr12:6521023 (GRCh38)
Gene constraint: LOEUF 0.687 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.94
Residue 543: the 'interactions with smc2 and smc4' region

Full NCAPD2 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

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NCAPD2 p.Arg1397His Uncertain significance ★★ ⚠ same condition
NCAPD2 p.Arg677His Uncertain significance ★★ ⚠ same condition
NCAPD2 p.Asn598Ile Uncertain significance ★★ ⚠ same condition
NCAPD2 p.Glu1178Lys Uncertain significance ★★ ⚠ same condition
NCAPD2 p.Glu883Lys Uncertain significance ★★ ⚠ same condition
NCAPD2 c.2482-6C>T 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/ncapd2-p-phe543val (accessed [today's date]).

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