Is APCDD1L p.Ser374Phe (c.1121C>T) pathogenic?

APCDD1L p.Ser374Phe (c.1121C>T) is classified Uncertain significance in APCDD1L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: ambiguous (0.4248); Very rare (popmax 0.00458%, nfe).

How common is APCDD1L p.Ser374Phe (c.1121C>T) in the general population?

APCDD1L p.Ser374Phe (c.1121C>T) is very rare (popmax 0.00458%, nfe) (gnomAD).

What do computational predictors say about APCDD1L p.Ser374Phe (c.1121C>T)?

AlphaMissense predicts ambiguous (score 0.4248) — an in-silico prediction, not a clinical call.

APCDD1L p.Ser374Phe

c.1121C>T · VCV3930738

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4248 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00458%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4248	ambiguous
REVEL	0.135	moderately benign-leaning
SaProt	LLR -12.36	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 54 kb · p 0.77 · regional, not allelic
Overall
CADD	18.26	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 0.00458% European (non-Finnish) · 54/1,179,652 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00376% 55/1,461,040 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00458%	21,845
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: APCDD1L
Protein: p.Ser374Phe
Coding: c.1121C>T
MANE Select: NM_153360
Type: single nucleotide variant
Location: chr20:58461175 (GRCh38)
Gene constraint: LOEUF 1.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.31

Full APCDD1L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APCDD1L p.Ala141Val Uncertain significance ★ ⚠ same type
APCDD1L p.Ala159Glu Uncertain significance ★ ⚠ same type
APCDD1L p.Ala246Ser Uncertain significance ★ ⚠ same type
APCDD1L p.Ala333Thr Uncertain significance ★ ⚠ same type
APCDD1L p.Ala3Ser Uncertain significance ★ ⚠ same type
APCDD1L p.Arg139His Uncertain significance ★ ⚠ same type
APCDD1L p.Arg139Pro Uncertain significance ★ ⚠ same type
APCDD1L p.Arg153Cys Uncertain significance ★ ⚠ 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/apcdd1l-p-ser374phe (accessed [today's date]).

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